Compound possessing affinity at 5ht1-type receptors and use thereof in therapy of cns disorders

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed:  
                 
wherein: 
 
A is optionally substituted phenyl, naphthyl, indolyl, quinolinyl, quinazolinyl, indazolyl, isoquinolinyl or benzofuranyl; X is carbon, Y is CH and  
                 
 
is a double bond; or X is CH, Y is CH 2  or oxygen and  
                 
 
is a single bond; or X is nitrogen, Y is CH 2  and  
                 
is a single bond; 
     is halogen, hydroxy, cyano, C 1-6 alkyl, haloC 1-6 alkyl or C 1-6 alkoxy; a is 0, 1, 2, 3 or 4;    R2 and R3, together with the nitrogen atom to which they are attached, form a nitro group or an optionally substituted 3 to 7 membered heterocyclic group, or R2 and R3 are independently hydrogen, aroyl, C 1-6 alkyl, C 1-6 alkanoyl, fluoroC 1-6 alkanoyl, C 1-6 alkylsulfonyl, fluoroC 1-6 alkylsulfonyl, carbamoyl, C 1-6 alkylcarbamoyl, arylC 1-6 alkyl or a group CO(CH 2 )bNR4R5 wherein b is 1, 2, 3 or 4; and R4 and R5 are independently hydrogen or C 1-6 alkyl, or R4 and R5, together with the nitrogen atom to they are attached, form part of an optionally substituted 3 to 7 membered heterocyclic group. Methods of preparing the compounds and uses of the compounds in therapy, in particular for CNS disorders such as depression and anxiety, are also disclosed.

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing the same and theiruse as medicaments in the treatment of CNS disorders and otherdisorders.

A novel series of compounds has now been found that possess highaffinity for 5-HT₁ type receptors. The present invention thereforeprovides, in a first aspect, a compound of formula (I) or apharmaceutically acceptable salt thereof:

-   -   wherein:

-   A is optionally substituted phenyl, naphthyl, indolyl, quinolinyl,    quinazolinyl, indazolyl, isoquinolinyl or benzofuranyl;

-   X is carbon, Y is CH and    is a double bond; or X is CH, Y is CH₂ or oxygen and    is a single bond; or X is nitrogen, Y is CH₂ and    is a single bond;

-   R1 is halogen, hydroxy, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl or    C₁₋₆alkoxy;

-   a is 0, 1, 2, 3 or 4;

-   R2 and R3, together with the nitrogen atom to which they are    attached, form a nitro group or an optionally substituted 3 to 7    membered heterocyclic group, or R2 and R3 are independently    hydrogen, aroyl, C₁₋₆alkyl, C₁₋₆alkanoyl, fluoroC₁₋₆alkanoyl,    C₁₋₆alkylsulfonyl, fluoroC₁₋₆alkylsulfonyl, carbamoyl,    C₁₋₆alkylcarbamoyl, arylC₁₋₆alkyl or a group CO(CH₂)_(b)NR4R5    wherein b is 1, 2, 3 or 4 and R4 and R5 are independently hydrogen    or C₁₋₆alkyl, or R4 and R5, together with the nitrogen atom to they    are attached, form part of an optionally substituted 3 to 7 membered    heterocyclic group.

The term “halogen” and its abbreviation “halo” refer to fluorine,chlorine, bromine or iodine.

The term “C₁₋₆alkyl” refers to an alkyl group having from one to sixcarbon atoms, in all isomeric forms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl,sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.

The term “haloC₁₋₆alkyl” refers to an alkyl group having one or moresubstitutions by halogen atoms, such as for example CF₃.

The term “C₁₋₆alkoxy” refers to a straight chain or branched chainalkoxy (or “alkyloxy”) group having from one to six carbon atoms, suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentoxy, neopentoxy, sec-pentoxy, n-pentoxy, isopentoxy,tert-pentoxy and hexoxy.

The term “C₁₋₆alkanoyl” refers to an alkanoyl group having from 1 to 6carbon atoms, such as methanoyl (or “formyl”), ethanoyl (or “acetyl”),propanoyl, isopropanoyl, butanoyl, isobutanoyl, sec-butanoyl, pentanoyl,neopentanoyl, sec-pentanoyl, isopentanoyl, tertpentanoyl and hexanoyl.

The term “fluoroC₁₋₆alkanoyl” refers to a fluorine-substitutedC₁₋₆alkanoyl group such as CF₃CO. The term “fluoroC₁₋₆alkylsulfonyl”refers to a fluorine-substituted C₁₋₆alkylsulfonyl group such as CF₃SO₂.

The term “carbamoyl” refers to the group H₂NCO. The term“C₁₋₆alkylcarbamoyl” refers to a group having the formula(C₁₋₆alkyl)HNCO, such as CH₃NHCO.

The term “aryl”, whether alone or as part of another group, is intended,unless otherwise stated, to denote an aromatic carbocyclic orheterocyclic group such as phenyl, naphthyl, thienyl, furyl, pyridyl,pyrimidinyl, isoxazolyl or pyrazinyl, optionally substituted by one ormore, preferably 1 to 3, halogen, C₁₋₆alkyl, CF₃, cyano, hydroxy,C₁₋₆alkanoyl, or C₁₋₆alkoxy. Where used herein the term naphthyl,whether alone or as part of another group, is intended, unless otherwisestated, to denote both 1-naphthyl and 2-naphthyl groups.

The term “aroyl” refers to the group aryl-CO— wherein “aryl” is asdefined above.

The term “oxo” refers to the group “═O”.

The term “optionally substituted 3 to 7 membered heterocyclic group”refers to an optionally substituted saturated or non-saturated ringcontaining at least one nitrogen atom and optionally a further 1 or 2heteroatoms selected from nitrogen, sulphur or oxygen, the ringconsisting of a total of 3 to 7 atoms. Examples of such heterocyclicgroups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, pyrrolyl,pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, thiazolyl, piperidyl,piperazinyl, morpholinyl, thiomorpholinyl, azepinyl and azepanyl. Theheterocyclic group may be substituted by one or more, preferably 1 to 3,substituents, which may be the same or different, and which is selectedfrom the following group: halogen, oxo, C₁₋₆alkyl, cyano, CF₃,C₁₋₆alkoxy and C₁₋₆alkanoyl. The optional substituent(s) may be attachedto any available carbon, nitrogen or sulphur atom. Substituents in theheterocyclic group may form a bridge structure, to form a group such asfor example 2-oxa-5-azabicyclo[2.2.1]heptyl. Such a bicyclic group maybe further substituted by one or more, preferably 1 to 3, halogen, oxo,C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy or C₁₋₆alkanoyl.

The term “C₃₋₇cycloalkylC₁₋₆alkoxy” refers to a cycloalkyl groupconsisting of from 3 to 7 carbon atoms (for example cyclopropane,cyclobutane, cyclopentane, cyclohexane and cycloheptane) attached to anarylC₁₋₆alkoxy group.

When a is two or more, the two or more R1 groups may be the same ordifferent.

A is optionally substituted phenyl, naphthyl, indolyl, quinolinyl,quinazolinyl, indazolyl, isoquinolinyl or benzofuranyl. These groups maybe attached to the oxygen atom at any suitable position. These groupsmay be substituted by 1 to 4 substituents, which may be the same ordifferent, and which are selected from the following group: halogen,hydroxy, cyano, CF₃, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkylsulfonyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyloxy, C₁₋₆alkylsulfonylC₁₋₆alkyl,C₁₋₆alkylsulfonamido, C₁₋₆alkylamido, C₁₋₆alkylsulfonamidoC₁₋₁₆alkyl andC₁₋₆alkylamidoC₁₋₆alkyl. Preferred optional substituents for A areC₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl.

Preferably A is quinolinyl or quinazolinyl. Most preferably, A is5-(2-methyl)quinolinyl or 5-(2-methyl)quinazolinyl.

Preferably Y is CH or CH₂.

Preferably a is 0, 1 or 2.

Preferably R1 is fluoro.

Preferably R2 and R3 are independently hydrogen, C₁₋₆alkyl (particularlymethyl, ethyl or propyl), C₁₋₆alkanoyl, C₁₋₆alkylsulfonyl,haloC₁₋₆alkanoyl or C₁₋₆alkylcarbamoyl. More preferably, one of R2 andR3 is hydrogen or C₁₋₆alkyl (particularly methyl, ethyl or propyl) andthe other is C₁₋₆alkanoyl, C₁₋₆alkylsulfonyl, fluoroC₁₋₆alkanoyl, orC₁₋₆alkylcarbamoyl, or R2 and R3, together with the nitrogen atom towhich they are attached, form a saturated 5 or 6 membered heterocyclicgroup such as piperazinyl, pyrrolidinyl, imidazolidinyl,isothiazolidinyl, thiazolidinyl, morpholinyl or piperidyl, optionallysubstituted by 1 or 2 substituent(s) selected from C₁₋₄alkyl and oxo.When R2 and/or R3 is a group CO(CH₂)bNR4R5, b is preferably 1. R4 and R5may form an optionally substituted 3 to 7 membered heterocyclic group,preferably a saturated 5 or 6 membered heterocylic group, such aspyrrolidinyl or piperidyl.

Preferred compounds of this invention are example compounds E1-E122 (asdescribed below) and pharmaceutically acceptable salts thereof.

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be hydrated orsolvated. This invention includes within its scope stoichiometrichydrates or solvates as well as compounds containing variable amounts ofwater and/or solvent.

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. geometric (or “cis-trans”) isomers,diastereomers and enantiomers) and the invention extends to each ofthese stereoisomeric forms and to mixtures thereof including racemates.The different stereoisomeric forms may be separated one from the otherby the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis. The invention also extends toany tautomeric forms and mixtures thereof. The present inventionincludes within its scope all such isomers, including mixtures.

In a further aspect, this invention provides a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, which process comprises:

-   (a) the coupling of a compound of formula (II):    wherein A is as defined for formula (I) and L is a leaving group,    and a compound of formula (III):    wherein a, R1, R2, R3, X, Y and    are as defined for formula (I); or-   (b) for a compound wherein X is nitrogen, the coupling of a compound    of formula (IV):    wherein A is as defined for formula (I), and a compound of formula    (V):    wherein a, R1, R2 and R3 are as defined for formula (I), or-   (c) a Buchwald reaction between a compound of formula (VI):    wherein L is a suitable leaving group and a, R1, X, Y and    are as defined for formula (I), and a compound of formula (VII):    wherein R2 and R3 are as defined for formula (I);    and thereafter optionally for process (a), (b) or (c):    -   removing any protecting groups and/or    -   converting a compound of formula (I) into another compound of        formula (I) and/or    -   forming a pharmaceutically acceptable salt.

For process (a), the reaction of compounds of formulae (II) and (III) ispreferably carried out in a suitable solvent such as isopropyl alcoholor N,N-dimethylformamide, in the presence of an appropriate base such asN,N-diisopropylethylamine or potassium carbonate. A suitable leavinggroup L is bromine.

For process (b), the reaction of compounds of formulae (IV) and (V) ispreferably carried out in an aprotic solvent such as 1,2-dichloroethane,in the presence of an appropriate reducing agent such as sodiumtriacetoxyborohydride.

Standard conditions for a Buchwald reaction may be used for process (c).Suitable leaving groups are bromine and triflate.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard techniques. For example, and by way ofillustration rather than limitation, for compounds of formula (I)wherein

is a double bond can be converted to compounds of formula (I) in which

is a single bond by palladium catalysed hydrogenation in a suitablesolvent such as ethanol. Other possible conversion reactions includeacylation with an appropriate acylating agent such as acetyl chloride,alkylation using an appropriate alkylating reagent such as methyliodide, and sulfonylation using a sulfonylating agent such asmethanesulfonic anhydride.

Compounds of formulae (II) to (VII) are commercially available, may beprepared according to procedures described herein, by known literaturemethods, or by analogous procedures thereto.

For example, for compounds of the present invention wherein X is carbonand

is a double bond, compounds of formula (III) wherein X is carbon may beprepared by reacting a compound of formula (VIII):

wherein “Alk” refers to an alkyl group, with a compound of formula (IX):

wherein Q is a protecting group such as t-butyloxycarbonyl, in thepresence of a base such as sodium hydride, in a solvent such astetrahydrofuran or N,N-dimethylformamide. The protecting group Q may beremoved thereafter by any suitable means.

Compounds of formula (VIII) may be prepared by treating a compound offormula (X):

wherein L is a leaving group such as bromine, with a trialkyl phosphitesuch as triethyl phosphite or trimethyl phosphite, in the absence ofsolvent or in the presence of a solvent such as toluene.

It will be appreciated by those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove procedures. Standard protection and deprotection techniques, suchas those described in Greene T.W. Protective groups in organicsynthesis, New York, Wiley (1981), can be used. For example, primaryamines can be protected as phthalimide, benzyl, t-butyloxycarbonyl,benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can beprotected as esters. Aldehyde or ketone groups can be protected asacetals, ketals, thioacetals or thioketals. Deprotection of such groupsis achieved using conventional procedures well known in the art. Forexample, protecting groups such as t-butyloxycarbonyl may be removedusing an acid such as hydrochloric or trifluroroacetic acid in asuitable solvent such as dichloromethane, diethylether, isopropanol ormixtures thereof.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

The affinities of the compounds of this invention for 5-HT_(1A),5-HT_(1B) and 5-HT_(1D) receptors can be determined by the radioligandbinding assay as described in WO 99/07700. All compounds testedaccording to the radioligand binding assay described above were found tohave pKi values >6.0 at 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptors,with many showing a considerably higher affinity (having pKi values inthe range 8.0-10.0).

The intrinsic activity of the compounds of this invention can bedetermined according to the [³⁵S]GTPγS functional assay which is alsodescribed in WO 99/07700. It has been found, using the [³⁵S]GTPγSfunctional assay, that certain compounds of formula (I) appear to beantagonists at 5-HT₁ type receptors whilst others appear to be inverseagonists, agonists or partial agonists.

Compounds of formula (I) and their pharmaceutically acceptable salts areof use in the treatment of certain CNS disorders such as depression(both bipolar and unipolar), single or recurrent major depressiveepisodes with or without psychotic features, catatonic features,melancholic features, atypical features or postpartum onset, seasonalaffective disorder and dysthymia, anxiety disorders, includinggeneralised anxiety, schizophrenia, panic disorder, agoraphobia, socialphobia, obsessive compulsive disorder and post-traumatic stressdisorder; pain (particularly neuropathic pain); memory disorders,including dementia, amnesic disorders and age-associated memoryimpairment; disorders of eating behaviours, including anorexia nervosaand bulimia nervosa, sexual dysfunction, sleep disorders (includingdisturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea andnarcolepsy), withdrawal from abuse of drugs such as of cocaine, ethanol,nicotine, benzodiazepines, alcohol, caffeine, phencyclidine(phencyclidine-like compounds), opiates (e.g. cannabis, heroin,morphine), sedative ipnotic, amphetamine or amphetamine-related drugs(e.g. dextroamphetamine, methylamphetamine) or a combination thereof,motor disorders such as Parkinson's disease, dementia in Parkinson'sdisease, neuroleptic-induced Parkinsonism and tardive dyskinesias, aswell as other psychiatric disorders. Depressive disorders which may betreated or prevented by the compounds of formula (I) and theirpharmaceutically acceptable salts may also result from a general medicalcondition including, but not limited to, myocardial infarction,diabetes, miscarriage or abortion, etc. Compounds of formula (I) mayalso have utility in the treatment of certain gastrointestinal disorderssuch as irritable bowel syndrome.

It is to be understood that “treatment” as used herein includesprophylaxis as well as alleviation of established symptoms.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment of the above disorders. Inparticular the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use as a therapeuticsubstance in the treatment of a CNS disorder, particularly depression oranxiety.

Compounds of the invention may be administered in combination with otheractive substances such as 5HT3 antagonists, serotonin agonists, NK-1antagonists, selective serotonin reuptake inhibitors (SSRI),noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressantsand/or dopaminergic antidepressants.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination orcomposition may be administered simultaneously (either in the same ordifferent pharmaceutical formulations), separately or sequentially.

The invention further provides a method of treatment of the abovedisorders, particularly a CNS disorder such as depression or anxiety, inmammals including humans, which comprises administering to the sufferera therapeutically safe and effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides for the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of the abovedisorders, particularly a CNS disorder such as depression or anxiety.

In order to use the compounds of formula (I) in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice. The present invention alsoprovides a pharmaceutical composition, which comprises a compound offormula (I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or excipient.

In a further aspect, the present invention provides a process forpreparing a pharmaceutical composition, the process comprising mixing acompound of formula (I) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); tabletting lubricants lubricants (e.g.magnesium stearate, talc or silica); disintegrants (e.g. potato starchor sodium starch glycollate); and acceptable wetting agents (e.g. sodiumlauryl sulphate). The tablets may be coated according to methods wellknown in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents (e.g. sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g. lecithin or acacia), non-aqueous vehicles (which may includeedible oils e.g. almond oil, oily esters, ethyl alcohol or fractionatedvegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoatesor sorbic acid), and, if desired, conventional flavourings or colorants,buffer salts and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. Formulations for injection may bepresented in unit dosage form e.g. in ampoules or in multi-dose,utilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle, optionally with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. The compound, depending on the vehicle and concentrationused, can be either suspended or dissolved in the vehicle. In preparingsolutions, the compound can be dissolved for injection and filtersterilised before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are dissolved in the vehicle. To enhance the stability,the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parenteral suspensions are prepared insubstantially the same manner, except that the compound is suspended inthe vehicle instead of being dissolved, and sterilisation cannot beaccomplished by filtration. The compound can be sterilised by exposureto ethylene oxide before suspension in a sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three times a day. Such therapymay extend for a number of weeks or months.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 1

Diethyl (3-nitrobenzyl)phosphonate (D1)

A mixture of 3-nitrobenzyl bromide (17.3 g, 0.08 mol), triethylphosphite (13.3 g, 0.08 mol) in toluene (200 mL) was stirred at refluxfor 24 h. The reaction mixture was cooled and evaporated in vacuo.Chromatography of the residues on SiO₂ eluting from 0-100% ethyl acetatein petroleum ether (60-80° C.) gave the title compound (14.8 g, 68%) asa yellow liquid.

Mass spectrum (API⁺): Found 274 (MH⁺). C₁₁H₁₆NO₅P requires 273.

¹H NMR (CDCl₃) δ: 1.28 (6H, m), 3.26 (2H, d, J=22 Hz), 4.11 (4H, m),7.51 (1H, t, J=8 Hz), 7.67 (1H, m), 8.15 (2H, m).

Description 1a

Diethyl (2-fluoro-4-methoxy-5-nitrobenzyl)phosphonate (D1a)

The title compound was prepared from 2-fluoro-4-methoxy-5-nitrobenzylbromide in an analogous fashion to Description 1.

Description 1b

Diethyl (3-fluoro-4-methoxy-5-nitrobenzyl)phosphonate (D1b)

The title compound was prepared from 3-fluoro-4-methoxy-5-nitrobenzylbromide in an analogous fashion to Description 1.

Description 2

tert-Butyl 4-(3-nitrobenzylidene)piperidine-1-carboxylate (D2)

A mixture of diethyl (3-nitrobenzyl)phosphonate (8.4 g, 0.031 mol) andtert-butyl 4-oxopiperidine-1-carboxylate (6.12 g, 0.031 mol) in drytetrahydrofuran (120 mL) was treated with a 60% suspension of sodiumhydride in oil (1.36 g, 0.034 mmol). The resulting mixture was stirredat room temperature for 4 h, then partitioned between dichloromethane(500 mL) and water (500 mL). The organic extract was dried (Na₂SO₄) andevaporated in vacuo to give the title compound (9.86 g, 100%) as asolid.

¹H NMR (CDCl₃) δ: 1.48 (9H, s), 2.38 (2H, m), 2.45 (2H, m), 3.43 (2H,m), 3.53 (2H, m), 6.39 (1H, s), 7.49 (2H, m), 8.06 (2H, m),

Description 3

4-(3-Nitrobenzylidene)piperidine hydrochloride (D3)

A mixture of tert-butyl 4-(3-nitrobenzylidene)piperidine-1-carboxylate(9.86 g, 0.031 mol), methanol (20 mL) and 1M HCl in diethyl ether (200mL) was stirred at 20° C. for 72 h. The reaction mixture was evaporatedin vacuo and the residue triturated in diethyl ether (3×100 mL) to givethe title compound (6.67 g, 85%) as a solid.

Mass spectrum (API⁺): Found 219 (MH⁺). C₁₂H₁₄N₂O₂ requires 218.

¹H NMR (d⁶DMSO) δ: 2.61 (2H, m), 2.65 (2H, m), 3.39 (1H, m), 3.90-4.04(4H, m), 6.58 (1H, s), 7.66 (1H, t, J=8 Hz), 7.72 (1H, m), 8.04 (1H, m),8.11 (1H, m), 9.40 (1H, bs).

Description 4

3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylidinemethyl)anilinedihydrochloride (D4)

A solution of3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylidene-methyl)nitrobenzene(0.48 g, 0.0012 mol) in glacial acetic acid (5 mL) was treated withreduced iron powder (0.2 g, 0.0036 mol). The mixture was stirred at 80°C. for 24 h, cooled and filtered through celite washing withdichloromethane. The filtrate was washed with 2 M sodium hydroxidesolution (20 mL). The organic layer was dried (Na₂SO₄) and evaporated invacuo. The residues were suspended in 2N HCl (10 mL) and stirred atreflux for 2 h, evaporated in vacuo and the residue triturated in etherto give the title compound (0.29 g, 54%) as a solid.

Mass spectrum (API⁺): Found 374 (MH⁺). C₂₄H₂₇N₃O requires 373.

¹H NMR (CD₃OD) δ: 2.72-2.84 (2H, m), 3.01 (5H, m), 3.22-3.39 (2H, m),3.87 (4H, m), 4.77 (2H, m), 4.83 (4H, bs), 6.62 (1H, s), 7.31 (2H, m),7.39 (1H, m), 7.44 (1H, d, J=8 Hz), 7.54 (1H, t, J=8 Hz), 7.77 (1H, d,J=9 Hz), 7.93 (1H, d, J=9 Hz), 8.09 (1H, t, J=8 Hz), 9.57 (1H, m),

Description 5

tert-Butyl(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)-carbamate(D5)

A mixture of3-(1-(2-(2-methylquinolin-5-yloxy)ethylpiperidin-4-ylmethyl)anilinedihydrochloride (0.3 g, 0.00067 mol), di-tert-butyldicarbonate (0.15 g,0.00067 mol) triethylamine (0.074 g, 0.00074 mol), tetrahydrofuran (2mL) and water (0.5 mL) was stirred at 20° C. for 18 h. The reactionmixture was partitioned between ethyl acetate (15 mL) and water (3×10mL). The organic layer was dried (Na₂SO₄) and evaporated in vacuo.Chromatography of the residues on SiO₄ eluting from 50-100% ethylacetate in petroleum ether (60-80° C.) gave the title compound (0.22 g,69%) as an oil.

Mass spectrum (API⁺): Found 476 (MH⁺). C₂₉H₃₇N₃O₃ requires 475.

¹H NMR (CDCl₃) δ: 1.33 (2H, m), 1.51 (9H, s), 1.67 (3H, m), 2.13 (2H,m), 2.51 (2H, d, J=7 Hz), 2.72 (3H, s), 2.92 (2H, m), 3.01 (2H, m), 4.27(2H, m), 6.45 (1H, br s), 6.80 (2H, m), 7.13-7.26 (4H, m), 7.56 (2H, m),8.43 (1H, d, J=9 Hz).

Description 6

4-Methyl-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}aniline(D6)

To a stirred solution of2-methyl-5-{2-[4-(2-methyl-5-nitrobenzylidene)piperidin-1-yl]ethoxy}quinoline(prepared using an analogous route and intermediates to Example 1; 0.21g, 0.51 mmol) in methanol (10 mL) was added concentrated hydrochloricacid (2.0 mL) and SnCl₂ (0.39 g, 2.04 mmol) and the mixture stirred atreflux under argon for 3 h. On cooling the mixture was evaporated invacuo, the residue partitioned between dichloromethane and water and thesuspension treated with 40% NaOH solution. The organic layers wereseparated, dried (Na₂SO₄) and evaporated in vacuo to give the titlecompound (0.19 g, 96%).

Mass spectrum (API⁺): Found 388 (MH⁺). C₂₅H₂N₃O requires 387.

The following compounds were similarly prepared:

-   (a)    2-Chloro-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}aniline-   (b)    4-Methoxy-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}aniline-   (c)    3-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-5-trifluoromethylaniline-   (d)    2-Methyl-3-{1-[242-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}aniline-   (e)    2-Chloro-3-{1-[2-(2-methyl-quinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}aniline-   (f)    2-Isopropyl-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}aniline-   (g)    5-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-2-trifluoromethylaniline-   (h)    3-Chloro-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}aniline    Description 7

2-Chloro-N-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)-acetamide(D7)

A mixture of3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride (0.15 g, 0.00033 mol) and triethylamine (0.17 g, 0.0017mol) in dichloromethane (5 mL) was treated with chloroacetyl chloride(0.037 g, 0.00033 mol) and stirred at 20° C. for 2 h. The mixture waswashed with water (5 mL), and the organic layer added directly ontoSiO₂. Elution from 0-10% methanol in ethyl acetate gave the titlecompound (0.11 g, 74%) as an oil.

Mass spectrum (API⁺): Found 452 (MH⁺). C₂₆H₃₀ ³⁵ClN₃O₂ requires 451.

¹H NMR (CDCl₃) δ: 1.40 (2H, m), 1.52-1.69 (3H, m), 2.17 (2H, m), 2.55(2H, d, J=7 Hz), 2.72 (3H, s), 2.97 (2H, m), 3.09 (2H, m), 4.18 (2H, s),4.31 (2H, m), 6.79 (1H, d, J=7 Hz), 6.95 (1H, d, J=8 Hz), 7.25 (2H, m),7.37 (2H, m), 7.57 (2H, m), 8.19 (1H, bs), 8.41 (1H, d, J=9 Hz).

Description 8

5-Fluoro-2-methyl-3,4-dihydroquinazoline (D8)

A solution of 2-amino-6-fluorobenzylamine (1.1 g, 7.86 mmol) andtriethylorthoacetate (1.58 mL, 8.64 mmol) in ethanol (30 mL) was heatedat 80° C. for 14 h. The reaction mixture was allowed to cool to roomtemperature and evaporated in vacuo. The yellow oil was triturated withdiethyl ether to give the title compound as white solid (0.74 g, 57%).

Mass spectrum (API⁺): Found 165 (MH⁺). C₉H₉N₂F requires 164.

¹H NMR (CDCl₃) δ: 2.02 (3H, s), 4.67 (2H, s), 6.34-6.71 (2H, m),7.03-7.12 (1H, m).

Description 9

5-Fluoro-2-methylquinazoline (D9)

To a solution of 5-fluoro-2-methyl-3,4-dihydroquinazoline (0.74 g, 4.51mmol) in chloroform (100 mL) at room temperature was added manganese(IV) oxide (4.0 g, 46.0 mmol) and the reaction mixture stirred at roomtemperature for 20 h. The reaction mixture was filtered through a plugof celite, washing with dichloromethane. The filtrate was evaporated invacuo to give the title compound as a yellow solid (0.715 g, 98%).

Mass spectrum (API⁺): Found 163 (MH⁺). C₉H₇N₂F requires 162.

¹H NMR (CDCl₃) δ: 2.92 (3H, s), 7.19-7.27 (1H, m), 7.77-7.83 (2H, m),9.60 (1H, s).

Description 10

2-(2-Methylquinazolin-5-yloxy)ethanol (D10)

To a solution of ethylene glycol (3.05 mL, 55.6 mmol) inN,N-dimethylformamide (50 mL) at room temperature was added sodiumhydride (60% dispersion in oil, 0.30 g, 7.50 mmol) portionwise. Thereaction mixture was allowed to stir at room temperature for 30 minutes.A solution of 5-fluoro-2-methylquinazoline (2.22 g, 55.6 mmol) inN,N-dimethylformamide (5 mL) was added and the reaction mixture heatedat 85° C. for 14 h.

The mixture was allowed to cool to room temperature, quenched by theaddition of water and concentrated in vacuo. Chromatography of theresidue on SiO₂ eluting with 40% ethyl acetate in dichloromethane toethyl acetate gave the title compound as a yellow solid (0.39 g, 10%).

Mass spectrum (API⁺): Found 205 (MH⁺) C₁₁H₁₂N₂O₂ requires 204.

¹H NMR (CDCl₃) δ: 2.87 (3H, s), 4.13-4.16 (2H, m), 4.31-4.33 (2H, m),6.88(1H, d, J=8 Hz), 7.50 (1H, d, J=9 Hz), 7.72-7.76 (1H, m), 9.64 (1H,s).

Description 11

5-[2-(Methanesulfonyloxy)ethoxy]-2-methylquinazoline (D11)

To a solution of 2-(2-methylquinazolin-5-yloxy)ethanol (0.330 g, 1.62mmol) in dichloromethane (20 mL) and triethylamine (0.34 mL, 2.43 mmol)was added methane sulfonyl chloride (0.14 mL, 1.78 mmol) dropwise. Thereaction mixture was allowed to stir at room temperature for 2 h. Thereaction mixture was diluted with further dichloromethane andpartitioned with saturated aqueous NaHCO₃ solution. The organic phasewas washed with brine, dried (MgSO₄) and evaporated in vacuo to give thetitle compound as a cream solid (0.452 g, 99%).

Mass spectrum (ES⁺): Found 283 (MH⁺) C₁₋₂H₁₄N₂O₄S requires 282.

¹H NMR (CDCl₃) δ: 2.89 (3H, s), 3.10 (3H, s), 4.46-4.48 (2H, m).4.71-4.73 (2H, m), 6.86 (1H, d, J=8 Hz), 7.55 (1H, d, J=9 Hz), 7.74-7.78(1H, m), 9.69(1H, s).

Description 12

2-Fluoro-4-methoxy-5-nitrobenzaldehyde (D12)

2-Fluoro-4-methoxy-benzaldehyde (36 g) was added to mechanically stirredconcentrated sulfuric acid (250 mL) at 0° C. The solution was maintainedat −15° C. while nitric acid (70% w/w) (22 g) was added dropwise.Further stirring was allowed for 45 mins. at this temperature before themixture was poured onto crushed ice (800 mL). The resulting precipitatewas collected by filtration and partitioned between dichloromethane (800mL) and saturated aqueous NaHCO₃ solution (1 L). The organic layer wasdried (Na₂SO₄) and evaporated in vacuo to give the title compound (44.2g, 95%) as a light yellow solid.

¹H NMR (CDCl₃) δ: 4.06 (3H, s), 6.87 (1H, d, J=12 Hz), 8.46 (1H, d, J=8Hz), 10.22 (1H, s).

Description 12a

3-Fluoro-4-methoxy-5-nitrobenzaldehyde (D12a)

The title compound was prepared in an analogous manner to Description12.

Description 13

2-Fluoro-4-methoxy-5-nitrobenzyl alcohol (D13)

Sodium borohydride (1.6 g) was added in portions to a stirring solutionof 2-fluoro-4-methoxy-5-nitrobenzaldehyde (5.35 g) in methanol (50 mL)at 0° C. The methanol was then removed in vacuo and the resultingresidue was partitioned between cold water (100 mL) and dichloromethane(200 mL). The organic layer was dried (Na₂SO₄) and evaporated in vacuo.The residue was purified by silica gel chromatography eluting with ethylacetate in hexane to give the title compound (3.35 g, 66%) as a lightyellow solid.

¹H NMR (CDCl₃) 8:1.85 (1H, t, J=6 Hz), 3.96 (3H, s), 4.74 (2H, d, J=6Hz), 6.87 (1H, d, J=12 Hz), 8.46 (1H, d, J=8 Hz).

Description 13a

(3-Fluoro-4-methoxy-5-nitrobenzyl alcohol (D13a)

The title compound was prepared in an analogous manner to Description13.

Description 14

1-tert-Butoxycarbonyl-4-(3-nitrophenoxy)piperidine (D14)

A stirred solution of 1-tert-butoxycarbonylpiperidin-4-ol (2.0 g, 10mmol), 3-nitrophenol (1.5 g, 11 mmol) and triphenylphosphine (5.2 g, 20mmol) in dry THF (40 mL) at 0° C. under argon was treated dropwise over10 minutes with diisopropyl azodicarboxylate (4.0 g, 20 mmol). Themixture was maintained at 20° C. for 2 h, then concentrated in vacuo.The residue was dissolved in diethyl ether (150 mL), washed with 1 MNaOH solution (100 mL) and dilute NaCl solution, then dried (Na₂SO₄) andconcentrated in vacuo. Chromatography of the residue on silica geleluting with 30-70% ether/60-80 petrol afforded a pale yellow oil (4.36g) containing the title compound in approximately 72% purity, togetherwith product from diisopropyl azodicarboxylate.

¹H NMR (CDCl₃) δ: 1.48 (9H, s), 1.73-1.82 (2H, m), 1.91-2.00 (2H, m),3.33-3.42 (2H, m), 3.67-3.75 (2H, m), 4.54-4.61 (1H, m), 7.23 (1H, dd),7.43 (1H, t), 7.73 (1H, t), 7.81 (1H, dd).

Description 15

4-(3-Nitrophenoxy)piperidine (D15)

The title compound was prepared from1-tert-butoxycarbonyl-4-(3-nitrophenoxy)piperidine using a similarprocedure to that described in Description 3.

Mass spectrum (API⁺): Found 223 (MH⁺). C₁₁H₁₄N₂O₃ requires 222.

Description 16

5-{2-[4-(3-Aminophenoxy)piperidin-1-yl]ethoxy}-2-methylquinoline (D16)

The title compound was prepared from5-{2-[4-(3-nitrophenoxy)piperidin-1-yl]ethoxy}-2-methylquinoline using asimilar procedure to that described in Example 2.

Mass spectrum (API⁺): Found 378 (MH⁺). C₂₃H₂₇N₃O₂ requires 377.

Description 17

5-[2-(4-Hydroxypiperidin-1-yl)ethoxy]-2-methylquinoline (D17)

The title compound was prepared from 5-(2-bromoethoxy)-2-methylquinolineand 4-hydroxypiperidine following the method of Example 1.

¹H NMR (CDCl₃) δ: 1.60-1.70 (2H, m), 1.88-1.98 (2H, m), 2.35-2.43 (2H,m), 2.73 (3H, s), 2.88-3.00 (2H, t+2H, m), 3.70-3.79 (1H, m), 4.27 (2H,t), 6.80 (1H, dd), 7.25 (1H, d), 7.53-7.62 (2H, m), 8.44 (1H, d). OH notdiscernible from spectrum.

Description 18

5-{2-[4-{4-Chloro-3-nitrophenoxy)piperidin-1-yl]ethoxy}-2-methylquinoline(D18)

The title compound was prepared from5-[2-(4-hydroxypiperidin-1-yl)ethoxy]-2-methylquinoline and theappropriate substituted phenol using a similar procedure to thatdescribed in Description 14.

Mass spectrum (API⁺): Found 442 (MH⁺). C₂₃H₂₄ ³⁵ClN₃O₄ requires 441.

Description 19

5-{2-[4-(3-Amino-4-chlorophenoxy)piperidin-1-yl]ethoxy}-2-methylquinoline(D19)

The title compound was prepared from5-{2-[4-(4-chloro-3-nitrophenoxy)piperidin-1-yl]ethoxy}-2-methylquinolineusing a similar procedure to that described in Example 2.

Mass spectrum (API⁺): Found 412 (MH⁺). C₂₃H₂₆ ³⁵ClN₃O₂ requires 411.

Description 20

Diethyl (3-bromobenzyl)phosphonate (D20)

The title compound was prepared from 3-bromobenzyl bromide in a similarmanner to description D1.

Mass spectrum (API⁺): Found 307 (MH⁺). C₁₁H₁₆ ⁷⁹BrPO₃ requires 306.

Description 21

tert-Butyl 4-(3-bromobenzylidene)piperidine-1-carboxylate (D21)

The title compound was prepared from diethyl (3-bromobenzyl)phosphonatein a similar manner to Description 2.

¹H NMR (CDCl₃) δ: 1.48 (9H, s), 2.33 (2H, m), 2.43 (2H, m), 3.41 (2H,m), 3.50 (2H, m), 6.29 (1H, s), 7.11 (1H, m), 7.18 (1H, t, J=8 Hz), 7.34(2H, m).

Description 22

4-(3-Bromobenzylidene)piperidine hydrochloride (D22)

The title compound was prepared from tert-butyl4-(3-bromobenzylidene)piperidine-1-carboxylate in a similar manner toDescription 3.

Mass spectrum (API⁺): Found 252 (MH⁺). C₁₂H₁₄ ⁷⁹BrN requires 251.

Description 23

3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)bromobenzene(D23)

The title compound was prepared from 4-(3-bromobenzylidene)piperidinehydrochloride in a similar manner to Description 25.

Mass spectrum (API⁺): Found 437 (MH⁺). C₂₄H₂₅ ⁷⁹BrN₂O requires 436.

Description 24

5-(2-(4-(3-Bromobenzylidene)piperidin-1-yl)ethoxy)-2-methylquinazoline(D24)

The title compound was prepared from 4-(3-bromobenzylidene)piperidinehydrochloride and 5-[2-(methanesulfonyloxy)ethoxy]-2-methylquinazolinein a similar manner to Description 25.

Mass spectrum (API⁺): Found 438 (MH⁺). C₂₃H₂₄ ⁷⁹BrN₃O requires 437.

Description 25

tert-Butyl 4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazine-1-carboxylate(D25)

tert-Butyl piperazine-1-carboxylate (1.4 g, 7.52 mmol) was added to amixture of 5-(2-bromoethoxy)-2-methylquinoline (2 g, 7.52 mmol) andpotassium carbonate (4.16 g, 30.1 mmol) in N,N-dimethylformamide (20mL). The reactants were heated at 70° C. for 16 h under an atmosphere ofargon. The reaction mixture was poured into water (200 mL) and extractedinto ethyl acetate (3×200 mL). The organic layers were combined, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by columnchromatography, eluting with 30% ethyl acetate in hexane affording thetitle compound as a tan solid (1.04 g, 37%).

Mass spectrum (API⁺): Found 372.3 (MH⁺). C₂₁H₂₉N₃O₃ requires 371.

¹H NMR (CDCl₃) δ: 1.46 (9H, s), 2.59 (4H, t), 2.73 (3H, s), 2.96 (2H,t), 3.46 (4H, t), 4.29 (2H, t), 6.80 (1H, dd), 7.26 (1H, d), 7.58 (2H,m), 8.43 (1H, d).

Description 26

2-Methyl-5-(2-piperazin-1-ylethoxy)quinoline (D26)

tert-Butyl 4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazine-1-carboxylate(1.04 g, 2.8 mmol) was dissolved in ethanol (60 mL) and treated with 1 Mhydrochloric acid in diethyl ether (16 mL, 16 mmol) and stirred at 40°C. for 17 h. The reaction mixture was filtered and the white solid wascollected and dried in vacuo. The hydrochloride salt precipitate wasdissolved in water (25 mL) and potassium carbonate was added until thepH reached 10. The aqueous layer was washed with 5% methanol indichloromethane (4×100 mL) then 10% methanol in dichloromethane (4×100mL). The organic layers were combined, dried (Na₂SO₄) and concentratedin vacuo, affording the title compound as a brown oil (0.69 g, 91%).

Mass spectrum (API⁺): Found 272 (MH⁺). C₁₆H₂₁N₃O requires 271.

¹H NMR (CDCl₃) δ: 2.62 (4H, m), 2.73 (3H, s), 2.92 (6H, m), 3.47 (1H,s), 4.29 (1H, d), 6.80 (1H, dd), 7.50 (1H, d), 7.58 (2H, m), 8.45 (1H,d). NH not discernible.

Description 27

2-(5-Quinolinyloxy)ethyl bromide (D27)

A mixture of 5-hydroxyquinoline (0.3 g, 2.1 mmol), 1,2-dibromoethane(3.9 g, 21 mmol) and potassium carbonate (1.5 g, 11 mmol) in methylethyl ketone (15 mL) was allowed to stir at 85° C. for 24 h. The mixturewas evaporated in vacuo and the residue was partitioned between ether(200 mL) and water (200 mL). The organic layer was dried (Na₂SO₄) andevaporated in vacuo to give the title compound (0.53 g).

¹H NMR (CDCl₃) δ: 3.80 (2H, m), 4.49 (2H, m), 6.86 (1H, d, J=8 Hz), 7.41(1H, dd, J=8, 4 Hz), 7.61 (1H, t, J=8 Hz), 7.73 (1H, d, J=8 Hz), 8.64(1H, d, J=8 Hz), 8.91 (1H, m).

Description 28

5-Hydroxy-2-methylquinoline (D28)

A mixture of 2-methyl-5,6,7,8-tetrahydroquinolin-5-one [E. Reimann, J.Freisinger, Arch. Pharm. (Weinheim), 318, 871 (1985)] (0.57 g, 3.5 mmol)and 48% aqueous HBr (3.5 mL) was warmed to 60° C. and treated dropwisewith bromine (0.19 mL, 0.59 g, 3.6 mmol), with vigorous stirring. Theresulting mixture was stirred at 60° C. for 1 h, then evaporated invacuo. The residue was treated with isopropanol with stirring, then themixture was evaporated in vacuo to give a waxy solid, which wastriturated with 1:1 isopropanol-ether to give a beige powder (0.9 g). Amixture of this material, lithium carbonate (0.48 g, 6.7 mmol), lithiumbromide (0.28 g, 3.2 mmol) and N,N-dimethylformamide (10 mL) was heatedat 150° C. under argon with stirring for 2 h. The mixture was cooledthen evaporated in vacuo. Chromatography of the residue on silica with0-100% ethyl acetate-hexane gradient elution gave the title compound(0.28 g, 49%) as a solid.

Mass spectrum (API⁺): Found 160 (MH⁺). C₁₀H₉NO requires 159.

Description 29

5-(2-Bromoethoxy)-2-methylquinoline (D29)

The title compound was prepared from 5-hydroxy-2-methylquinoline and1,2-dibromoethane using a similar procedure to Description 27, in 91%yield.

Mass spectrum (API⁺): Found 266 (MH⁺). C₁₂H₁₂ ⁷⁹BrNO requires 265.

Description 30

5-Bromo-2-methoxy-3-nitrobenzyl Bromide (D30)

Sodium borohydride (4 g) was added in portions to a stirring solution ofcrude 5-bromo-2-methoxy-3-nitrobenzaldehyde (20.5 g) in methanol (350mL) and tetrahydrofuran (150 mL) at 0° C. After 1 h, the methanol wasremoved in vacuo. The residue was treated with cold water (150 mL) andextracted with diethyl ether (2×150 mL). The combined organic layer wasevaporated in vacuo to give a crude oil. Silica gel chromatographyeluting with ethyl acetate in petroleum ether (10-40%) gave the titlecompound (17 g) as a solid.

¹HNMR (CDCl₃): 2.00 (1H, t, J=6 Hz), 3.92 (3H, s), 4.80 (2H, d, J=6 Hz),7.84 (1H, d, J=2 Hz), 7.91 (1H, d, J=2 Hz).

Description 31

5-Bromo-2-methoxy-3-nitrobenzyl Alcohol (D31)

2,6-Lutidine (10.5 mL) was added to a stirring solution of5-bromo-2-methoxy-3-nitrobenzyl alcohol (13.6 g) and lithium bromide(11.75 g) in anhydrous tetrahydrofuran (200 mL) at 0° C. A solution ofmethanesulfonic anhydride (11.8 g) in anhydrous tetrahydrofuran (20 mL)was added dropwise. The resulting mixture was left to stir at roomtemperature for 16 h. It was partitioned between diethyl ether (250 mL)and saturated sodium hydrogen carbonate (150 mL). The organic layer wasdried (sodium sulfate) and evaporated in vacuo. Silica gelchromatography of the crude residue eluting with diethyl ether inpetroleum ether gave the title compound (20 g) as an amber oil.

¹H NMR (CDCl₃) δ: 4.06 (3H, s), 4.48 (2H, s), 7.76 (1H, d, J=2 Hz), 7.93(1H, d, J=2 Hz).

The following two compounds were prepared in an analogous manner toDescription 31:

Description 31a

2-Fluoro-4-methoxy-5-nitrobenzyl Bromide (D31a)

Description 31b

3-Fluoro-4-methoxy-5-nitrobenzyl Bromide (D31b)

Description 32

8-Chloro-4-hydroxy-5-methoxy-2-(trifluoromethyl)quinoline (D32)

A mixture of 2-chloro-5-methoxyaniline hydrochloride (10.0 g, 0.063 mol)and ethyl (trifluoromethyl)acetoacetate (10.3 mL, 0.070 mol) inpolyphosphoric acid (40 mL) was heated to 160° C. under argon for 2 h.Water (200 mL) was added with care and the crude product extracted(EtOAc×2). Chromatography (SiO₂; eluant 20% 60-80° petrol/EtOAc)afforded the title compound as a dark yellow solid (3.38 g, 19%).

¹H NMR (400 MHz, CDCl₃) δ: 4.13 (s, 3H), 6.85 (d, 1H), 7.19 (s, 1H),7.75 (d, 1H), 10.05 (s, 1H).

Description 33

4,8-Dichloro-5-methoxy-2-(trifluoromethyl)quinoline (D33)

A mixture of 8-chloro-4-hydroxy-5-methoxy-2-(trifluoromethyl)quinoline(3.38 g, 0.012 mol) and phosphorus pentachloride (2.08 g, 0.01 mol) inphosphorus oxychloride (20 mL) was heated at reflux for 2.5 h. Oncooling, water (100 mL) was added with care and the product extracted(CH₂Cl₂×2). The organics were dried (Na₂SO₄) and evaporated in vacuo togive the title compound as a yellow solid (3.19 g, 90%).

¹H NMR (400 MHz, CDCl₃) δ: 4.00 (s, 3H), 6.97 (d, 1H), 7.79 (s, 1H),7.85 (d, 1H).

Description 34

5-Methoxy-2-(trifluoromethyl)quinoline (D34)

A solution of 4,8-dichloro-5-methoxy-2-(trifluoromethyl)quinoline (2.9g, 9.8 mmol) in 1M ethanolic potassium hydroxide (100 mL) washydrogenated over 10% palladium on carbon (50% aqueous paste; 500 mg) atatmospheric temperature and pressure for 18 h. The mixture was filteredthrough celite, the filtrate evaporated in vacuo and the residuepartitioned between CH₂Cl₂ and water. The organics were dried (Na₂SO₄)and evaporated in vacuo. Chromatography (SiO₂; eluant 20% EtOAc/60-80°petrol) afforded the title compound as a yellow solid (850 mg, 38%).

¹H NMR (400 MHz, CDCl₃) δ: 4.04 (s, 3H), 6.96 (d, 1H), 7.70-7.73 (m,2H), 7.80 (d, 1H), 8.76 (d, 1H).

Description 35

2-(Trifluoromethyl)quinolin-5-ol (D35)

To a solution of 5-methoxy-2-(trifluoromethyl)quinoline (830 mg, 3.65mmol) in CH₂Cl₂ (20 mL) at 0° C. was added dropwise boron tribromide(1.0 mL, 10.95 mmol). The mixture was stirred under argon whilstallowing to warm to room temp. for 2 h. Water (50 mL) was added withcare and the organics separated, dried (Na₂SO₄) and evaporated in vacuoto give a pale yellow oil (570 mg, 73%).

¹H NMR (400 MHz, CDCl₃) δ: 5.97 (br s, 1H), 6.97 (d, 1H), 7.63 (t, 1H),7.73 (d, 1H), 7.82 (d, 1H), 8.77 (d, 1H).

Description 36

5-(2-Bromoethoxy)-2-(trifluoromethyl)quinoline (D36)

A mixture of 2-(trifluoromethyl)quinolin-5-ol (563 mg, 2.64 mmol),potassium carbonate (1.8 g, 13.0 mmol) and 1,2-dibromoethane (2.3 mL,26.0 mmol) in methyl ethyl ketone (20 mL) was heated at reflux underargon for 16 h. The solvent was removed in vacuo and the residuepartitioned between water and CH₂Cl₂. The organics were dried (Na₂SO₄)and evaporated. Chromatography (SiO₂; eluant 20% to 50% EtOAc/60-80⁰petrol) afforded the title compound as a buff solid (600 mg, 71%).

¹H NMR (400 MHz, CDCl₃) δ: 3.80 (t, 2H), 4.52 (t, 2H), 6.95 (d, 1H),7.69-7.74 (m, 2H), 7.84 (d, 1H), 8.82 (d, ₁H).

Description 37

C-[(2-Hydroxyethyl)methylamino]-N-(3-1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamide(D37)

The title compound was prepared from2-chloro-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamidein a manner similar to Example 46.

Mass spectrum (API⁺): Found 491. C₂₉H₃₈N₄O₃ requires 490.

Description 38

C-[Benzyl-(2-hydroxyethyl)amino]-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamide(D38)

The title compound was prepared from2-chloro-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamidein a manner similar to Example 46.

Mass spectrum (API⁺): Found 567. C₃₅H₄₂N₄O₃ requires 566.

Description 39

C-[(2-Chloroethyl)methylamino]-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamide(D39)

Methanesulfonyl chloride (40 mg, 0.35 mmol) was added to a solution ofC-[(2-hydroxyethyl)methylamino]-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamide(170 mg, 0.35 mmol), in pyridine (2 ml) and stirred, under argon, atambient temperature for 1 h. The reaction mixture was partitionedbetween ethyl acetate (5 ml) and water (5 ml). The organic layer wasremoved and dried over Na₂SO₄, filtered and the solvent removed in vacuoto give the title compound (130 mg, 74%) as a brown oil.

Mass spectrum (API⁺): Found 509. C₂₉H₃₇ ³⁵ClN₄O₂ requires 508.

Description 40

C-[Benzyl-(2-chloroethyl)amino]-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamide(D40)

The title compound was prepared fromC-[benzyl-(2-hydroxyethyl)amino]-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamidein a manner similar to Description 39.

Mass spectrum (API⁺): Found 585. C₃₅H₄₁ ³⁵ClN₄O₂ requires 584.

Description 41

tert-Butyl 4-(3-iodobenzylidene)piperidine-1-carboxylate (D41)

The title compound was prepared in a manner analogous to tert-butyl4-(3-bromobenzylidene)piperidine-1-carboxylate (Description 22).

1H NMR (CDCl₃) δ: 1.48 (9H, s), 2.32 (2H, m), 2.42 (2H, m), 3.40 (2H,m), 3.50 (2H, m), 6.26 (1H, s), 7.04 (1H, J 8), 7.14 (1H, m), 7.54 (2H,m).

Description 42

tert-Butyl 4-(3-pyrazol-1-ylbenzylidene)piperidine-1-carboxylate (D42)

A mixture of tert-butyl 4-(3-iodobenzylidene)piperidine-1-carboxylate(500 mg, 1.25 mmol), pyrazole (95 mg, 1.4 mmol), copper (I) iodide (5mol %, 12 mg, 0.06 mmol), trans-1,2-diaminocyclohexane (10 mol %, 14 mg,0.13 mmol), and potassium phosphate (530 mg, 2.5 mmol) in 1,4-dioxan (5ml) was stirred at 110° C. for 24 h. The reaction mixture was cooled toroom temperature and partitioned between ethyl acetate (10 ml) and water(10 ml). The organic layer was separated and evaporated to dryness invacuo. The residue was purified by SiO₂ chromatography on a 10 gpre-packed column, eluting from 30-100% ethyl acetate in petroleum ether(60-80° C.) to give the title compound (65 mg, 15%) as a colourless oil.

Mass spectrum (API⁺): Found 340. C₂₀H₂₅N₃O₂ requires 339.

Description 43

4-(3-Pyrazol-1-ylbenzylidene)piperidine (D43)

The title compound was prepared from tert-butyl4-(3-pyrazol-1-ylbenzylidene)piperidine-1-carboxylate in a mannersimilar to Description 3.

Mass spectrum (API⁺): Found 240. C₁₅H₁₇N₃ requires 239.

Description 44

tert Butyl 4-(3-bromo-4-fluorobenzylidene)piperidine-1-carboxylate (D44)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Description 21.

Mass spectrum (API⁺): Found 270. C₁₇H₂₁BrFNO₂ requires 370.

Description 45

tert butyl4-[4-fluoro-3-(4-methylpiperazin-1-yl)benzylidene]piperidine-1-carboxylate(45)

The title compound was prepared from tert butyl4-(3-bromo-4-fluorobenzylidene)piperidine-1-carboxylate using the methodof Example 58.

Description 46

1-(2-Fluoro-5-(piperidin-4-ylidenemethyl)phenyl)-4-methylpiperazine(D46)

The title compound was prepared from tert butyl4-[4-fluoro-3-(4-methyl-piperazin-1-yl)-benzylidene]-piperidine-1-carboxylateusing the method of Description 3.

Mass spectrum (API⁺): Found 290. C₁₇H₂₄FN3 requires 289.

Description 47

1-(2-Fluoro-5-(piperidin-4-ylmethyl)phenyl)-4-methylpiperazine (D47)

The title compound was prepared from1-(2-fluoro-5-(piperidin-4-ylidenemethyl)phenyl)-4-methylpiperazineusing the method of Example 1.

Mass spectrum (API⁺): Found 292 (MH⁺). C₁₇H₂₆N₃F requires 291.

¹H NMR (400 MHz, CDCl₃) δ1.24-1.36 (2H, m), 1.59-1.64 (1H, m br), 1.68(2H, d J 13.8), 2.35 (3H, s), 2.48 (2H, d J 7.0), 2.61 (4H, t J 4.7),2.63 (2H, d J 12.2), 3.11 (4H, t J 4.7), 3.17 (2H, d J 12.2), 4.63 (1H,s br), 6.68 (2H, m), 6.91 (1H, m).

Description 48

tert-Butyl 4-cyano-4-(3-nitrobenzyl)piperidine-1-carboxylate (D48)

A stirred solution of diisopropylamine (0.58 g, 5.8 mmol) in dry THF (30ml) at −60° C. under argon was treated with 1.6M n-butyllithium inhexane (3.2 ml, 5.2 mmol) and maintained at −60° C. for 10 minutes. Themixture was treated with a solution of tert-butyl4-cyanopiperidine-1-carboxylate (1.0 g, 4.8 mmol) in THF and maintainedat this temperature for a further 15 minutes, then treated with asolution of 3-nitrobenzyl bromide (1.08 g, 5 mmol) in THF and solutionkept at this temperature for 30 minutes. The mixture was allowed toreach room temperature and stir for one hour before the addition ofNH₄Cl solution (10 ml). The resulting mixture was concentrated in vacuoand the aqueous treated with 10% Na₂CO₃ solution and extracted withethyl acetate. The extract was dried (Na₂SO₄) and solvent removed invacuo to afford a brown oil, which was chromatographed on silica geleluting with 10-40% ethyl acetate/60-80 petrol to afford the titlecompound as a clear gum. (255 mg, 15%).

Mass spectrum (API⁺): Found 246 (MH⁺). C₁₈H₂₃N₃O₄ requires 345.

¹H NMR (400 MHz, CDCl₃) δ 1.46 (9H, s), 1.54 (2H, br), 1.83-1.87 (2H,br), 2.98 (2H, s), 2.99 (2H, br), 4.20 (2H, br), 7.56 (1H, t J 8.0),7.68 (1H, d J 7.6), 8.11 (1H, s), 8.19 (1H, d J 8.4).

Description 49

5-Hydroxyquinoline-N-oxide (D49)

A stirred suspension of 5-hydroxyquinoline (1.0 g, 6.9 mmol) in DCM (20ml) at room temperature was treated with a solution of3-chloroperbenzoic acid (8.0 mmol) in DCM (15 ml). After 2 h theprecipitate was filtered off, washed with DCM and dried to afford thetitle compound as a white solid (1.0 g, 90%).

¹H NMR (d⁶DMSO) δ: 7.07 (1H, d), 7.38 (1H, dd), 7.60 (1H, t), 7.97 (1H,d), 8.02 (1H, d), 8.54 (1H, d), 10.88 (1H, s).

Description 50

5-Hydroxyquinoline-2-carbonitrile (D50)

A stirred mixture of 5-hydroxyquinoline-N-oxide (1.0 g, 6.2 mmol),sodium cyanide (0.60 g, 12 mmol) and triethylamine (3.1 g, 31 mmol) inDMF (12 ml) at room temperature under argon was treated dropwise over0.5 h with chlorotrimethylsilane (2.9 g, 24 mmol), then heated at 100°C. for 3 h. The cooled mixture was filtered, then concentrated undervacuum and the residue treated with methanol (40 ml) and maintained atroom temperature for 40 mins, then concentrated under vacuum. Theresidue was chromatographed on silica gel eluting with DCM/ether toafford the title compound as a yellow solid (0.44 g, 42%).

¹H NMR (d⁶DMSO) δ: 7.11 (1H, d), 7.59 (1H, d), 7.74 (1H, t), 7.95 (1H,d), 8.73 (1H, d), 10.92 (1H, s).

Description 51

5-(2-Bromoethoxy)quinoline-2-carbonitrile (D51)

A stirred mixture of 5-hydroxyquinoline-2-carbonitrile (0.27 g, 1.6mmol), potassium carbonate (0.66 g, 4.8 mmol) and 1,2-dibromoethane (3.0g, 16 mmol) in 2-butanone (30 ml) was heated at reflux for 4 h, thenconcentrated under vacuum. The residue was treated with water andextracted with ethyl acetate. The extract was dried (Na₂SO₄),concentrated under vacuum and chromatographed on silica gel eluting with20-50% ethyl acetate/60-80 petrol, followed by crystallisation from 20%ethyl acetate/60-80 petrol, to afford the title compound as pale yellowsolid (0.27 g, 63%).

Mass spectrum (API⁺): Found 277/279 (MH⁺). C₁₂H₉BrN₂O requires 276/278.

¹H NMR (CDCl₃) δ: 3.80 (2H, t), 4.50 (2H, t), 6.98 (1H, d), 7.68-7.82(m, 3H), 8.78 (1H, d).

Description 52

3-{1-[2-(2-Cyanoquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}bromobenzene(D52)

A mixture of 5-(2-bromoethoxy)quinoline-2-carbonitrile (100 mg, 0.36mmol), 4-(3-bromobenzylidene)piperidine hydrochloride (0.42 mmol),potassium carbonate (150 mg, 1.1 mmol) and sodium iodide (165 mg, 1.1mmol) in DMF (5 ml) was stirred at room temperature for 48 h, thenconcentrated under vacuum and the residue treated with 10% sodiumcarbonate solution and extracted with ethyl acetate. The extract wasdried (Na₂SO₄), concentrated under vacuum and the residuechromatographed on silica gel eluting with ethyl acetate to afford thetitle compound as a yellow oil (140 mg, 87%).

Mass spectrum (API⁺): Found 448/450 (MH⁺). C₂₄H₂₂BrN₃O requires 447/449.

¹H NMR (CDCl₃) δ: 2.40-2.46 (2H, m), 2.50-2.55 (2H, m), 2.58-2.64 (2H,m), 2.70-2.76 (2H, m), 2.97 (2H, t), 4.33 (2H, t), 6.23 (1H, s), 7.00(1H, dd), 7.08-7.13 (1H, m), 7.13-7.20 (1H, m), 7.29-7.36 (2H, m),7.64-7.78 (3H, m), 8.70 (1H, d).

EXAMPLE 13-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)nitrobenzene(E1)

A mixture of 5-(2-bromoethoxy)-2-methylquinoline (0.52 g, 1.95 mmol),4-(3-nitrobenzylidene)piperidine hydrochloride (0.5 g, 1.96 mmol), andpotassium carbonate (0.83 g, 5.97 mmol) in N,N-dimethylformamide (5 mL)was stirred at 100° C. for 16 h. The reaction mixture was cooled andpartitioned between ethyl acetate (25 mL) and water (3×20 mL). Theorganic layer was dried (Na₂SO₄) and evaporated in vacuo. Chromatographyof the residue on SiO₂ eluting with 30-100% ethyl acetate in hexane gavethe title compound (0.62 g, 78%) as an oil.

Mass spectrum (API⁺): Found 404 (MH⁺). C₂₄H₂₅N₃O₃ requires 403.

¹H NMR (CDCl₃) δ: 2.47 (2H, m), 2.54 (2H, m), 2.66 (2H, m), 2.73 (3H,s), 2.77 (2H, m), 2.99 (2H, m), 4.30 (2H, m), 6.33 (1H, s), 6.82 (1H, d,J=7 Hz), 7.26 (1H, m), 7.50 (2H, m), 7.58 (2H, m), 8.05 (2H, m), 8.44(1H, d, J=8 Hz).

EXAMPLE 23-(1-(2-(2-(Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride (E2)

A mixture of3-(1-(2-(2-methylquinolin-5-yloxy)piperidin-4-ylidenemethyl)nitrobenzene(0.99 g, 2.46 mmol) and 10% palladium on charcoal (paste) (0.1 g) inmethanol (40 mL) was stirred at 20° C., under an atmosphere of hydrogen(1 atm) for 24 h. The reaction mixture was filtered through celite andthe filtrate treated with 1M HCl in ether (10 mL) and evaporated invacuo to give the title compound (1.10 g, 100%) as a solid.

Mass spectrum (API⁺): Found 376 (MH⁺). C₂₄H₂N₃O requires 375.

¹H NMR (CD₃OD) δ: 1.78 (2H, m), 1.93 (2H, m), 2.01 (1H, m), 2.72 (2H,m), 3.01 (3H, m), 3.21 (2H, m), 3.76 (4H, m), 4.73 (2H, m), 4.84 (4H,m), 7.27 (2H, m), 7.36 (1H, m), 7.42 (1H, d, J=8 Hz), 7.48 (1H, t, J=8Hz), 7.77 (1H, m), 7.92 (1H, d, J=8 Hz), 8.07 (1H, m), 9.52 (1H, d, J=9Hz).

EXAMPLE 3N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)methanesulfonamide(E3)

A mixture of3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride (0.17 g, 0.38 mmol) and triethylamine (0.15 g, 1.49mmol) in dichloromethane (8 mL) was treated with methanesulfonicanhydride (0.073 g, 0.42 mmol) and stirred at 20° C. for 1 h. Thereaction mixture was washed with water (5 mL) and the organic layerseparated and added to SiO₂, eluting from 0-15% methanol in ethylacetate gave the title compound (0.084 g, 49%) as an oil.

Mass spectrum (API⁺): Found 454 (MH⁺). C₂₅H₃₁N₃O₃S requires 453.

¹H NMR (CDCl₃) δ: 1.36 (2H, m), 1.54 (1H, m), 1.64 (2H, m), 2.14 (2H,m), 2.53 (2H, d, J=7 Hz), 2.72 (3H, s), 2.93 (2H, m), 3.00 (3H, s), 3.04(2H, m), 4.27 (2H, m), 6.78 (1H, d, J=7 Hz), 6.96 (1H, d, J=8 Hz), 7.04(2H, m), 7.24 (2H, m), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 4N-Methyl-N-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)methanesulfonamide(E4)

A solution ofN-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)methanesulfonamide(0.03 g, 0.066 mmol) in dry tetrahydrofuran (6 mL) was treated with a60% suspension of sodium hydride in oil (0.01 g, 025 mmol) and themixture stirred at 20° C. for 0.2 h. Methyl iodide (0.05 g, 0.35 mmol)was added and the mixture stirred for a further 1 h. The reactionmixture was partitioned between ethyl acetate (15 mL) and water (3×10mL) and the organic layer was evaporated in vacuo. Chromatography of theresidue on SiO₂ eluting from 0-15% methanol in ethyl acetate gave thetitle compound (0.0067 g, 22%) as an oil.

Mass spectrum (API⁺): Found 468 (MH)⁺. C₂₆H₃₃N₃O₃S requires 467.

¹H NMR (CDCl₃) δ: 1.41 (2H, m), 1.57 (1H, m), 1.67 (2H, m), 2.20 (2H,m), 2.56 (2H, m), 2.73 (3H, s), 2.84 (3H, s), 2.97 (2H, m), 3.08 (2H,m), 3.31 (3H, s), 4.30 (2H, m), 6.79 (1H, d, J=7 Hz), 7.08 (1H, d, J=8Hz), 7.18 (1H, m), 7.27 (3H, m), 7.57 (2H, m), 8.42 (1H, d, J=9 Hz).

EXAMPLE 51-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)pyrrolidin-2-one(E5)

A mixture of3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinehydrochloride (0.2 g, 0.45 mmol) and triethylamine (0.15 g, 1.49 mmol)in dichloromethane (10 mL) was treated with 4-bromobutyryl chloride(0.093 g, 0.5 mmol) and stirred at 20° C. for 1 h. The reaction mix waswashed with water (10 mL) and the organic layer separated, dried(Na₂SO₄) and evaporated in vacuo to give an oil (0.2 g) which wasdissolved in tetrahydrofuran (10 mL) and treated with a 60% dispersionof sodium hydride in oil (16 mg, 0.4 mmol). The mixture was stirred at20° C. for 18 h, then partitioned between ethyl acetate (20 mL) andwater (3×10 mL) and the organic layer was evaporated in vacuo.Chromatography of the residue on SiO₂ eluting with 0-20% methanol inethyl acetate gave the title compound (0.086 g, 43%) as an oil.

Mass spectrum (API⁺): Found 444 (MH⁺). C₂₈H₃₃N₃O₂ requires 443.

¹H NMR (CDCl₃) δ: 1.35 (2H, m), 1.56 (1H, m), 1.68 (2H, m), 2.15 (4H,m), 2.51 (2H, m), 2.72 (3H, s), 2.75 (2H, m), 2.92 (2H, m), 3.03 (2H,m), 4.27 (2H, m), 4.31 (2H, m), 6.79 (1H, d, J=7 Hz), 6.84 (1H, m), 6.93(1H, m), 7.22 (3H, m), 7.56 (2H, m), 8.43 (1H, d, J=8 Hz).

EXAMPLE 6N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)acetamide(E6)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 418 (MH⁺). C₂₅H₃₁N₃O₂ requires 417.

¹H NMR (CDCl₃) δ: 1.61 (3H, m), 1.71 (2H, m), 2.18 (3H, s), 2.40 (2H,m), 2.52 (2H, m), 2.73 (3H, s), 3.15 (2H, m), 3.27 (2H, m), 4.44 (2H,m), 6.81 (1H, d, J=7 Hz), 6.85 (1H, m), 7.19 (1H, m), 7.26 (1H, m), 7.33(1H, m), 7.38 (1H, m), 7.55 (1H, m), 7.63 (2H, m), 8.39 (1H, d, J=8 Hz).

EXAMPLE 7N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-ylmethyl)phenyl)propionamide(E7)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 432 (MH⁺). C₂₇H₃₃N₃O₂ requires 431.

¹H NMR (CDCl₃) 8:1.26 (3H, m), 1.56 (3H, m), 1.70 (2H, m), 2.36 (4H, m),2.53 (2H, m), 2.73 (3H, s), 3.11 (2H, m), 3.23 (2H, m), 4.40 (2H, m),6.80 (1H, d, J=8 Hz), 6.85 (1H, m), 7.20 (1H, m), 7.28 (2H, m), 7.35(1H, m), 7.42 (1H, m), 7.55 (1H, t, J=8 Hz), 7.62 (1H, d, J=8 Hz), 8.40(1H, d, J=9 Hz).

EXAMPLE 8N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)isobutyramide(E8)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 446 (MH⁺). C₂₈H₃₅N₃O₂ requires 445.

¹H NMR (CDCl₃) δ: 1.24 (6H, d, J=7 Hz), 1.34 (2H, m), 1.53 (1H, m), 1.65(2H, m), 2.13 (2H, m), 2.47 (1H, m), 2.51 (2H, m), 2.72 (3H, s), 2.92(2H, m), 3.02 (2H, m), 4.26 (2H, m), 6.78 (1H, m), 6.87 (1H, m), 7.21(3H, m), 7.33 (1H, m), 7.44 (1H, m), 7.56 (2H, m), 8.43(1H, d, J=9 Hz).

EXAMPLE 9N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)-2,2,2-trifluoroacetamide(E9)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 472 (MH⁺). C₂₆H₂₈F₃N₃O₂ requires 471.

¹H NMR (COCl₃) δ: 1.34 (2H, m), 1.54 (1H, m), 1.63 (2H, m), 2.13 (2H,m), 2.54 (2H, d, J=7 Hz), 2.71 (3H, s), 2.92 (2H, m), 3.02 (2H, m), 4.26(2H, m), 6.79 (1H, d, J=7 Hz), 7.01 (1H, d, J=8 Hz), 7.26 (2H, m), 7.39(2H, m), 7.56 (2H, m), 8.31 (1H, bs), 8.43 (1H, d, J=9 Hz).

EXAMPLE 10N-Methyl-N-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenylacetamide (E10)

The title compound was prepared fromN-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)acetamidefollowing a method analogous to that of Example 4.

Mass spectrum (API⁺): Found 432 (MH⁺). C₂₇H₃₃N₃O₂ requires 431.

¹H NMR (CDCl₃)δ: 1.37 (2H, m), 1.56 (1H, m), 1.66 (2H, m), 1.89 (3H, s),2.16 (2H, m), 2.57 (2H, d, J=7 Hz), 2.72 (3H, s), 2.94 (2H, m), 3.05(2H, m), 3.26 (3H, s), 4.28 (2H, m), 6.79 (1H, d, J=7 Hz), 6.97 (1H, m),7.01 (1H, m), 7.11 (1H, m), 7.28 (2H, m), 7.57 (2H, m), 8.43 (1H, d, J=8Hz).

EXAMPLE 11N-Ethyl-N-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)acetamide(E11)

The title compound was prepared fromN-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)acetamidefollowing a method analogous to that of Example 4.

Mass spectrum (API⁺): Found 446 (MH⁺). C₂₈H₃₅N₃O₂ requires 445.

¹H NMR (CDCl₃) δ: 1.11 (3H, t, J=7 Hz), 1.35 (2H, m), 1.56 (1H, m), 1.65(2H, m), 1.81 (3H, s), 2.15 (2H, m), 2.57 (2H, d, J=7 Hz), 2.72 (3H, s),2.93 (2H, m), 3.04 (2H, m), 3.73 (2H, q, J=7 Hz), 4.27 (2H, m), 6.79(1H, d, J=8 Hz), 6.93 (1H, s), 6.98 (1H, m), 7.12 (1H, m), 7.24 (1H, d,J=9 Hz), 7.32 (1H, t, J=8 Hz), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 121-Ethyl-3-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)urea(E12)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 447 (MH⁺). C₂₇H₃₄N₄O₂ requires 446.

¹H NMR (CDCl₃) δ: 1.10 (3H, m), 1.29 (2H, m), 1.53 (1H, m), 1.62 (2H,m), 2.10 (2H, m), 2.46 (2H, d, J=7 Hz), 2.72 (3H, s), 2.90 (2H, m), 3.00(2H, m), 3.25 (2H, m), 4.25 (2H, m), 5.34 (1H, m), 6.78 (2H, m), 7.07(1H, m), 7.15 (2H, m), 7.24 (2H, m), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 13N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)phenyl)acetamide(E13)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)anilnedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 416 (MH⁺). C₂₆H₂₅N₃O₂ requires 415.

¹H NMR (CDCl₃) δ: 2.14 (3H, s), 2.40 (2H, m), 2.53 (2H, m), 2.59 (2H,m), 2.72 (5H, m), 2.95 (2H, m), 4.28 (2H, m), 6.25 (1H, s), 6.80 (1H, d,J=7 Hz), 6.93 (1H, m), 7.24 (2H, m), 7.33 (1H, m), 7.42 (1H, m), 7.57(2H, m), 7.89 (1H, bs), 8.45 (1H, d, J=8 Hz).

EXAMPLE 14N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)ethanesulfonamide(E14)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 468 (MH⁺). C₂₈H₃₃N₃O₃S requires 467.

¹H NMR (CDCl₃) δ: 1.36 (3H, m), 1.45 (2H, m), 1.61 (1H, m), 1.68 (2H,m), 2.27 (2H, m), 2.54 (2H, m), 2.72 (3H, s), 3.04 (2H, m), 3.12 (4H,m), 4.33 (2H, m), 6.80 (1H, d, J=8 Hz), 6.93 (1H, m), 7.04 (2H, m), 7.24(2H, m), 7.57 (2H, m), 8.41 (1H, d, J=8 Hz).

EXAMPLE 15N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)trifluoromethanesulfonamide(E15)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 508 (MH⁺). C₂₅H₂₈F₃N₃O₃S requires 507.

¹H NMR (DMSO-d⁶) δ: 1.24 (2H, m), 1.76 (3H, m), 2.41 (2H, m), 2.64 (3H,s), 3.17 (2H, d, J=5 Hz), 3.60 (2H, m), 4.08 (2H, m), 4.46 (2H, m), 6.54(1H, m), 6.78 (2H, m), 6.95 (1H, m), 7.02 (2H, m), 7.41 (1H, m), 7.52(1H, m), 7.62 (1H, m), 8.48 (1H, m).

EXAMPLE 16N-(341-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)phenyl)isobutyramide(E16)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-yldienemethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 444 (MH⁺). C₂₈H₃₃N₃O₂ requires 443.

¹H NMR (CDCl₃) δ: 1.25 (6H, d, J=7 Hz), 2.42 (2H, m), 2.50 (1H, m), 2.56(2H, m), 2.63 (2H, m), 2.73 (5H, m), 2.97 (2H, m), 4.29 (2H, m), 6.26(1H, s), 6.81 (1H, d, J=7 Hz), 6.94 (1H, m), 7.25 (3H, m), 7.33 (1H, m),7.44 (1H, bs), 7.57 (2H, m), 8.44 (1H, d, J=9 Hz).

EXAMPLE 17N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)phenyl)methanesulfonamide(E17)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-yldienemethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 452 (MH⁺). C₂₅H₂₉N₃O₃S requires 451.

¹H NMR (CDCl₃) δ: 2.43 (2H, m), 2.53 (2H, m), 2.64 (2H, m), 2.73 (3H,s), 2.74 (2H, m), 2.98 (2H, m), 3.01 (3H, s), 4.30 (2H, m), 6.25 (1H,s), 6.81 (1H, d, J=7 Hz), 7.04 (3H, m), 7.27 (2H, m), 7.57 (2H, m), 8.44(1H, d, J=9 Hz).

EXAMPLE 181-Ethyl-3-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)phenyl)urea(E18)

The title compound was prepared from3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-yldienemethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 445 (MH⁺). C₂₇H₃₂N₄O₂ requires 444.

¹H NMR (CDCl₃) δ: 1.12 (3H, m), 2.40 (2H, m), 2.53 (2H, m), 2.58 (2H,m), 2.72 (5H, m), 2.96 (2H, m), 3.20 (2H, m), 4.28 (2H, m), 5.03 (1H,m), 6.22 (1H, s), 6.85 (3H, m), 7.13 (2H, m), 7.23 (2H, m), 7.57 (2H,m), 8.44 (1H, d, J=8 Hz).

EXAMPLE 191-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)imidazolidin-2-one(E19)

The title compound was prepared from3(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 5.

Mass spectrum (API⁺): Found 445 (MH⁺). C₂₇H₃₂N₄O₂ requires 444.

¹H NMR (CDCl₃) δ: 1.33 (2H, m), 1.56 (1H, m), 1.67 (2H, m), 2.14 (2H,m), 2.55 (2H, m), 2.72 (3H, s), 2.92 (2H, m), 3.03 (2H, m), 3.56 (2H,m), 3.94 (2H, m), 4.27 (2H, m), 4.62 (1H, bs), 6.79 (1H, d, J=8 Hz),6.85 (1H, m), 7.24 (2H, m), 7.31 (1H, m), 7.41 (1H, m), 7.56 (2H, m),8.43 (1H, d, J=8 Hz).

EXAMPLE 20N-341-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)thiophene-2-carboxamide(E20)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 486 (MH⁺). C₂₉H₃₁N₃O₂S requires 485.

¹H NMR (CDCl₃) δ: 1.35 (2H, m), 1.56 (1H, m), 1.67 (2H, m), 2.14 (2H,m), 2.54 (2H, d, J=7 Hz), 2.72 (3H, s), 2.92 (2H, m), 3.02 (2H, m), 4.27(2H, m), 6.79 (1H, d, J=7 Hz), 6.93 (1H, d, J=8 Hz), 7.11 (1H, m), 7.25(2H, m), 7.38 (1H, m), 7.48 (1H, m), 7.58 (4H, m), 7.77 (1H, bs), 8.43(1H, d, J=9 Hz).

EXAMPLE 21N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)furan-2-carboxamide(E21)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 470 (MH⁺). C₂₉H₃₁N₃O₃ requires 469.

¹H NMR (CDCl₃) 8:1.36 (2H, m), 1.57 (1H, m), 1.68 (2H, m), 2.14 (2H, m),2.55 (2H, d, J=7 Hz), 2.72 (3H, s), 2.92 (2H, m), 3.03 (2H, m), 4.27(2H, m), 6.55 (1H, m), 6.79 (1H, d, J=7 Hz), 6.93 (1H, d, J=8 Hz), 7.25(3H, m), 7.44 (1H, m), 7.50 (1H, m), 7.56 (3H, m), 8.06 (1H, bs), 8.43(1H, d, J=8 Hz).

EXAMPLE 22N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)pyridine-3-carboxamide(E22)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 481 (MH⁺). C₃₀H₃₂N₄O₂ requires 480.

¹H NMR (CDCl₃) δ: 1.36 (2H, m), 1.55 (1H, m), 1.67 (2H, m), 2.14 (2H,m), 2.55 (2H, d, J=7 Hz), 2.71 (3H, s), 2.93 (2H, m), 3.04 (2H, m), 4.27(2H, m), 6.78 (1H, dd, J=7, 2 Hz), 6.96 (1H, d, J=8 Hz), 7.26 (2H, m),7.41 (2H, m), 7.48 (1H, m), 7.57 (2H, m), 8.19 (2H, m), 8.43 (1H, d, J=9Hz), 8.75 (1H, dd, J=5, 2 Hz), 9.09 (1H, d, J=2 Hz).

EXAMPLE 23N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)isoxazole-5-carboxamide(E23)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 471 (MH⁺). C₂₈H₃₀N₄O₃ requires 470.

¹H NMR (CDCl₃) δ: 1.36 (2H, m), 1.57 (1H, m), 1.68 (2H, m), 2.15 (2H,m), 2.57 (2H, d, J=7 Hz), 2.72 (3H, s), 2.93 (2H, m), 3.04 (2H, m), 4.27(2H, m), 6.79 (1H, m), 7.02 (2H, m), 7.28 (2H, m), 7.45-7.61 (4H, m),8.22 (1H, bs), 8.42 (2H, m).

EXAMPLE 24N-(341-(242-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)pyridine-4-carboxamide(E24)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 481 (MH⁺). C₃₀H₃₂N₄O₂ requires 480.

¹H NMR (CDCl₃) δ: 1.39 (2H, m), 1.57 (1H, m), 1.68 (2H, m), 2.18 (2H,m), 2.57 (2H, d, J=7 Hz), 2.72 (3H, s), 2.95 (2H, m), 3.06 (2H, m), 4.28(2H, m), 6.79 (1H, dd, J=7, 2 Hz), 6.98 (1H, d, J=8 Hz), 7.27 (2H, m),7.46 (2H, m), 7.57 (2H, m), 7.70 (2H, m), 7.95 (1H, bs), 8.42 (1H, d,J=9 Hz), 8.79 (2H, m).

EXAMPLE 25N-(3-(1-2-2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)propane-2-sulfonamide(E25)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 482 (MH⁺). C₂₇H₃₅N₃O₃S requires 481.

¹H NMR (CDCl₃) δ:1.40 (8H, m), 1.55 (1H, m), 1.65 (2H, m), 2.19 (2H, m),2.53 (3H, m), 2.72 (3H, s), 2.97 (2H, m), 3.08 (2H, m), 4.29 (2H, m),6.77-6.93 (3H, m), 7.03 (1H, m), 7.22 (3H, m), 7.56 (2H, m), 8.42 (1H,d, J=9 Hz).

EXAMPLE 26 N-Methyl-N-(3-(1(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)phenyl)methanesulfonamide(E26)

The title compound was prepared fromN-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)phenyl)methanesulfonamidefollowing a method analogous to that of Example 4.

Mass spectrum (API⁺): Found 466 (MH⁺). C₂₆H₃₁N₃O₃S requires 465.

¹H NMR (CDCl₃) δ: 2.44 (2H, m), 2.55 (2H, m), 2.65 (2H, m), 2.75 (5H,m), 2.84 (3H, s), 2.99 (2H, m), 3.32 (3H, s), 4.31 (2H, m), 6.28 (1H,s), 6.81 (1H, m), 7.13 (1H, d, J=8 Hz), 7.21 (1H, m), 7.26 (2H, m), 7.33(1H, t, J=8 Hz), 7.57 (2H, m), 8.45 (1H, d, J=9 Hz)

EXAMPLE 275-(2-(4-(3-(1,1-Dioxo-1-isothiazolidin-2-yl)benzyl)piperidin-1-yl)ethoxy)-2-methylquinoline(E27)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 5.

Mass spectrum (API⁺): Found 480 (MH⁺). C₂₇H₃₃N₃O₃S requires 479.

¹H NMR (CDCl₃) δ: 1.36 (2H, m), 1.56 (1H, m), 1.67 (2H, m), 2.16 (2H,m), 2.52 (4H, m), 2.72 (3H, s), 2.95 (2H, m), 3.06 (2H, m), 3.70 (2H, t,J=8 Hz), 3.77 (2H, t, J=7 Hz), 4.28 (2H, m), 6.79 (1H, d, J=7 Hz), 6.93(1H, m), 7.06 (2H, m), 7.25 (2H, m), 7.56 (2H, m), 8.42 (1H, d, J=9 Hz).

EXAMPLE 28N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)propane-1-sulfonamide(E28)

The title compound was prepared from3-(1-(2-(2-(methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride following a method analogous to that of Example 3.

Mass spectrum (API⁺): Found 482 (MH⁺). C₂₇H₃₅N₃O₃S requires 481.

¹H NMR (CDCl₃) δ: 1.01 (3H, m), 1.33 (2H, m), 1.55 (1H, m), 1.64 (2H,m), 1.85 (2H, m), 2.14 (2H, m), 2.53 (2H, d, J=7 Hz), 2.72 (3H, s), 2.93(2H, m), 3.05 (4H, m), 4.27 (2H, m), 6.79 (1H, d, J=8 Hz), 6.94 (1H, d,J=8 Hz), 6.99 (1H, s), 7.02 (1H, m), 7.24 (2H, m), 7.56 (2H, m), 8.42(1H, d, J=8 Hz).

EXAMPLE 29N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)methylamine(E29)

A solution of tert-butyl(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)carbamate(0.22 g, 0.46 mmol) in dry tetrahydrofuran (10 mL) was cooled to <0° C.(ice/methanol). A 1.0M solution of lithium aluminium hydride in diethylether (1 mL, 1 mmol) was added dropwise with stirring and under argon.The mixture was allowed to warm up to 20° C. and then stirred at refluxfor 24 h. The reaction mixture was cooled and treated with 1N aqueoussodium hydroxide (2 mL), then partitioned between ethyl acetate (15 mL)and water (2×10 mL). The organic layer was dried (Na₂SO₄) and evaporatedin vacuo. Chromatography of the residue on SiO₂ eluting from 0-10%methanol in ethyl acetate gave the title compound (0.12 g, 67%) as anoil.

Mass spectrum (API⁺): Found 390 (MH⁺). C₂₅H₃₁N₃O requires 389.

¹H NMR (CDCl₃) δ: 1.33 (2H, m), 1.54 (1H, m), 1.69 (2H, m), 2.13 (2H,m), 2.46 (2H, d, J=7 Hz), 2.72 (3H, s), 2.82 (3H, s), 2.92 (2H, m), 3.03(2H, m), 4.27 (2H, m), 6.39 (1H, d, J=2 Hz), 6.45 (1H, dd, J=7, 2 Hz),6.51 (1H, d, J=7 Hz), 6.79 (1H, dd, J=8, 1 Hz), 7.09 (1H, t, J=8 Hz),7.23 (1H, d, J=9 Hz), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 30 N-Methyl-N-(3-(1 (2-(2-methylquinolin-5-yloxy)ethyl)piperidinylmethyl)phenyl)propane-2-sulfonamide (E30)

A mixture ofN-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)methylamine(0.092 g, 0.24 mmol), isopropylsulfonyl chloride (0.27 g, 1.92 mmol) inpyridine (3 mL) was stirred at 85° C. for 5 h. Reaction mix was cooledand partitioned between dichloromethane (5 mL) and water (5 mL) and theorganic layer was evaporated in vacuo. Chromatography of the residue onSiO₂ eluting from 0-15% methanol in ethyl acetate gave the titlecompound (0.037 g, 31%) as an oil.

Mass spectrum (API⁺): Found 496 (MH⁺). C₂₈H₃₇N₃O₃S requires 495.

¹H NMR (CDCl₃) δ: 1.38 (8H, m), 1.57 (1H, m), 1.68 (2H, m), 2.22 (2H,m), 2.56 (2H, d, J=7 Hz), 2.73 (3H, s), 3.00 (2H, m), 3.12 (2H, m), 3.28(1H, m), 3.36 (3H, s), 4.31 (2H, m), 6.80 (1H, d, J=8 Hz), 7.03 (1H, d,J=7 Hz), 7.24 (4H, m), 7.57 (2H, m), 8.42 (1H, d, J=9 Hz).

EXAMPLE 31N-(2-Fluoro-5-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)methanesulfonamide(E31)

The title compound was prepared using an analogous route andintermediates to those used to prepare Example 3.

Mass spectrum (API⁺): Found 472 (MH⁺). C₂₅H₃₀FN₃O₃S requires 471.

¹H NMR (CDCl₃) δ: 1.36 (2H, m), 1.59 (1H, m), 1.64 (2H, m), 2.15 (2H,m), 2.57 (2H, d, J=7 Hz), 2.72 (3H, s), 2.92 (2H, m), 2.97 (3H, s), 3.03(2H, m), 4.26 (2H, m), 6.79 (1H, dd, J=7, 1 Hz), 7.02 (3H, m), 7.24 (1H,d, J=9 Hz), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 325-{2-[4-(2-Fluoro-5-nitrobenzylidene)piperidin-1-yl]ethoxy}-2-methylquinoline(E32)

The title compound was prepared using an analogous route andintermediates to those used to prepare Example 1.

Mass spectrum (API⁺): Found 422 (MH⁺). C₂₄H₂₄FN₃O₃ requires 421.

¹H NMR (CDCl₃) δ: 2.44-2.51 (4H, m), 2.68 (2H, t J=6 Hz), 2.72 (3H, s),2.78 (2H, t, J=6 Hz), 3.00 (2H, t, J=6 Hz), 4.30 (2H, t, J=6 Hz), 6.19(1H, s), 6.80 (1H, d, J=9 Hz), 7.15-7.20 (1H, m), 7.25-7.27 (1H, m),7.54-7.62 (2H, m), 8.08-8.11 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 33N-(4-Fluoro-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)methanesulfonamide(E33)

The title compound was prepared from5-{2-[4-(2-fluoro-5-nitrobenzylidene)piperidin-1-yl]ethoxy}-2-methylquinolinefollowing method analogous to that of Example 3.

Mass spectrum (API⁺): Found 472 (MH⁺). C₂₅H₃₀FN₃O₃S requires 471.

¹H NMR (CDCl₃) δ: 1.26-1.38 (2H, m), 1.56-1.66 (3H, m), 2.12-2.18 (2H,m), 2.57 (2H, d, J=7 Hz), 2.73 (3H, s), 2.93 (2H, t, J=6 Hz), 3.02 (3H,s), 3.05-3.29 (2H, m), 4.27 (2H, t, J=6 Hz), 6.78-6.80 (1H, m),7.00-7.06 (2H, m), 7.23-7.26 (3H, m), 7.53-7.61 (2H), 8.42 (1H, d, J=9Hz).

EXAMPLE 34N-(4-Methyl-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4ylidenemethyl}phenyl)methanesulfonamide (E34)

The title compound was prepared from4-methyl-3{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}anilineusing analogous methods to Example 3.

Mass spectrum (API⁺): Found 466 (MH⁺). C₂₆H₃₁N₃O₃S requires 465.

¹H NMR (400 MHz, CDCl₃) δ: 2.22 (3H, s), 2.35 (2H, t), 2.44 (2H, t),2.62 (2H, t), 2.73 (3H, s), 2.75 (2H, t), 2.97 (3H, s), 2.98 (2H, t),4.29 (2H, t), 6.19 (1H, s), 6.35 (1H, br, s), 6.81 (1H, d), 6.99 (2H,d), 7.14 (1H, d), 7.26 (1H, d), 7.53-7.61 (2H, m), 8.44 (1H, d).

EXAMPLE 35N-(4-Methoxy-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)methanesulfonamide(E35)

The title compound was prepared from4-methoxy-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}anilineusing analogous methods to Example 3.

Mass spectrum (API⁺): Found 482 (MH⁺). C₂₆H₃₁N₃O₄S requires 481.

¹H NMR (400 MHz, CDCl₃) δ: 2.46 (4H, br m), 2.67 (2H, t), 2.73 (3H, s),2.76 (2H, t), 2.94 (3H, s), 2.99 (2H, t), 3.82 (3H, s), 4.30 (2H, t),6.25 (1H, s), 6.82 (2H, m), 7.04-7.10 (2H, m), 7.26 (1H, d), 7.59-7.67(1H, m), 7.55 (1H, m), 8.45 (1H, d). NH not discernible.

EXAMPLE 36N-(3-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-5-trifluoromethylphenyl)methanesulfonamide(E36)

The title compound was prepared from3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-5-trifluoromethylanilineusing methods analogous to Example 3.

Mass spectrum (API⁺): Found 520 (MH⁺). C₂₆H₂₈F₃N₃O₃S requires 519.

¹H NMR (400 MHz, CDCl₃) δ: 2.44 (2H, t), 2.51 (2H, t), 2.66 (2H, t),2.73 (3H, s), 2.76 (2H, t), 2.99 (2H, t), 3.05 (3H, s), 4.30 (2H, t),6.26 (1H, s), 6.81 (1H, d), 7.26 (4H, m), 7.53-7.61 (2H, m), 8.44 (1H,d). NH not discernible.

EXAMPLE 37N-(2-Methyl-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)methanesulfonamide(E37)

The title compound was prepared from2-methyl-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}anilineusing methods analogous to Example 3.

Mass spectrum (API⁺): Found 466 (MH⁺). C₂₆H₃₁N₃O₃S requires 465.

¹H NMR (400 MHz, CDCl₃) δ 2.22 (3H, s), 2.29 (2H, t), 2.42 (2H, t), 2.59(2H, t), 2.72 (3H, s), 2.74 (2H, t), 2.98 (2H, t), 3.01 (3H, s), 4.29(2H, t), 6.22 (1H, s), 6.80 (1H, d), 6.99 (1H, d), 7.14 (1H, t), 7.23(1H, s), 7.32 (1H, d), 7.53-7.61 (2H, m), 8.43 (1H, d). NH notdiscernible.

EXAMPLE 38N-(2-Chloro-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)methanesulfonamide(E38)

The title compound was prepared from2-chloro-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}anilineusing methods analgous to Example 3.

Mass spectrum (API⁺): Found 486 (MH⁺). C₂₅H₂₈ ³⁵ClN₃O₃S requires 485.

¹H NMR (400 MHz, CDCl₃) δ: 2.40 (2H, t), 2.48 (2H, t), 2.64 (2H, d),2.73 (3H, s), 2.78 (2H, t), 3.00 (2H, t), 3.03 (3H, s), 4.30 (2H, t),6.26 (1H, s), 6.80 (1H, d), 6.87 (1H, br, s), 7.06 (1H, d), 7.25 (2H,m), 7.53-7.62 (3H, m), 8.44 (1H, d).

EXAMPLE 39N-(2-Chloro-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)methanesulfonamide(E39)

The title compound was prepared from2-chloro-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}anilineusing methods analogous to Example 3.

Mass spectrum (API⁺): Found 486 (MH⁺). C₂₅H₂₈ ³⁵ClN₃O₃S requires 485.

¹H NMR (400 MHz, CDCl₃) δ 2.43 (2H, t), 2.53 (2H, t), 2.66 (3H, t), 2.73(3H, s), 2.75 (2H, t), 2.99 (2H, t), 3.00 (3H, s), 4.30 (1H, t), 6.81(1H, d), 6.97 (1H, d) 7.23 (1H, s), 7.26 (1H, d), 7.34 (1H, d), 7.48(1H, m), 7.49-7.59 (1H, m), 7.61-7.67 (1H, m), 8.46 (1H, d). NH notdiscernible.

EXAMPLE 40N-(2-isopropyl-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)methanesulfonamide(E40)

The title compound was prepared from2-isopropyl-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}anilineusing methods analogous to Example 3.

Mass spectrum (API⁺): Found 494 (MH⁺). C₂₈H₃₅N₃O₃S requires 493.

¹H NMR (400 MHz, CDCl₃) δ: 1.25 (6H, d), 2.42 (2H, t), 2.56 (2H, t),2.65 (2H, t), 2.73 (3H, s), 2.75 (2H, t), 2.97 (2H, t), 3.02 (3H, s),3.08-3.14 (1H, m), 4.30 (2H, d), 6.20 (1H, s), 6.24 (1H, s), 6.81 (1H,d), 7.09 (1H, d), 7.25-7.29 (3H, m), 7.54-7.61 (2H, m), 8.45 (1H, d).

EXAMPLE 41N-(5-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-2-trifluoromethylphenyl)methanesulfonamide(E41)

The title compound was prepared from5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-2-trifluoromethylanilineusing methods analogous to Example 3.

Mass spectrum (API⁺): Found 520 (MH⁺). C₂₆H₂₈N₃O₃SF₃ requires 519.

¹H NMR (400 MHz, CDCl₃) δ: 2.45 (2H, t), 2.56 (2H, t), 2.68 (2H, t),2.73 (3H, s), 2.75 (2H, t), 2.99 (2H, t), 3.00 (3H, s), 4.30 (2H, t),6.28 (1H, s), 6.80 (1H, d), 7.12 (1H, d), 7.27 (1H, d), 7.53-7.62 (3H,m), 7.65 (1H, s), 8.44 (1H, d). NH not discernible.

EXAMPLE 42N-(5-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}-2-trifluoromethylphenyl)methanesulfonamide(E42)

The title compound was prepared fromN-(5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-2-trifluoromethylphenyl)methanesulfonamideusing methods analogous to Example 2.

Mass spectrum (API⁺): Found 522 (MH⁺). C₂₆H₃₀F₃N₃O₃S requires 521

¹H NMR (400 MHz, CDCl₃) δ: 1.34-1.40 (3H, br m), 1.59-1.66 (2H, t), 2.15(2H, t), 2.61 (2H, d), 2.73 (3H, s), 2.93 (2H, t), 2.99 (3H, s), 3.03(2H, t), 4.26 (2H, t), 6.79 (1H, d), 7.08 (1H, d), 7.24 (2H, d),7.53-7.61 (3H, m), 8.42 (1H, d). NH not discemible.

EXAMPLE 43N-(4-Methyl-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)methanesulfonamide(E43)

The title compound was prepared fromN-(4-methyl-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)methanesulfonamideusing methods analogous to Example 2.

Mass spectrum (API⁺): Found 468 (MH⁺). C₂₆H₃₃N₃O₃S requires 467.

¹H NMR (400 MHz, CDCl₃) δ: 1.36-1.43 (2H, br t), 1.51-1.55 (1H, br m),1.65 (2H, t), 2.11-2.17 (2H, br, t), 2.23 (3H, s), 2.53 (2H, d), 2.73(3H, s), 2.93 (2H, t), 2.97 (3H, s), 3.04 (2H, t), 4.27(2H, t), 6.79(1H, d), 6.96 (1H, d), 7.11 (1H, d), 7.25 (2H, d), 7.53-7.61 (2H, m),8.43 (1H, d). NH not observed.

EXAMPLE 44N-(2-Isopropyl-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)methanesulfonamide(E44)

The title compound was prepared fromN-(2-isopropyl-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)methanesulfonamideusing methods analogous to Example 2.

Mass spectrum (API⁺): Found 496 (MH⁺). C₂₈H₃₇N₃O₃S requires 495.

¹HNMR (400 MHz, CDCl₃) δ: 1.24 (6H, d), 1.37 (2H, t), 1.53-1.68 (3H, m),2.16 (2H, t), 2.52 (2H, d), 2.73 (3H, s), 2.93 (2H, t), 3.00 (3H, s),3.03-3.08 (2H, t), 3.11 (1H, m), 4.27 (2H, t), 6.17 (1H, br, s), 6.79(1H, d), 7.03 (1H, d), 7.23 (3H, m), 7.53-7.60 (2H, m), 8.43 (1H, m).

EXAMPLE 45N-((3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)-2-dimethylamino)acetamide(E45)

A mixture of3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)anilinedihydrochloride (0.072 g, 0.16 mmol) and triethylamine (0.081 g, 0.8mmol) in dichloromethane (5 mL) was treated with dimethylaminoacetylchloride hydrochloride (0.025 g, 0.16 mmol) and the mixture stirred at20° C. for 2 h. Reaction mixture was washed with water (5 mL) and theorganic layer added to SiO₂. Eluting with 0-10% methanol in ethylacetate gave the title compound (0.041 g, 56%) as an oil.

Mass spectrum (API⁺): Found 461 (MH⁺). C₂₈H₃₆N₄O₂ requires 460.

¹H NMR (CDCl₃) δ: 1.36 (2H, m), 1.57 (1H, m), 1.68 (2H, m), 2.17 (2H,m), 2.38 (6H, s), 2.54 (2H, d, J=7 Hz), 2.72 (3H, s), 2.95 (2H, m), 3.07(4H, m), 4.29 (2H, m), 6.79 (1H, d, J=7 Hz), 6.89 (1H, d, J=8 Hz), 7.24(2H, m), 7.40 (2H, m), 7.56 (2H, m), 8.42 (1H, d, J=9 Hz), 9.04 (1H,bs).

EXAMPLE 46N-((3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)-2-diethylamino)acetamide(E46)

A mixture of2-chloro-N-(3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)acetamide(0.055 g, 0.00012 mol), diethylamine (0.01 g, 0.00013 mol), sodiumiodide (0.018 g, 0.00012 mol) and N,N-diisopropylethylamine (0.048 g,0.00037 mol) in isopropanol (5 mL) was stirred at reflux for 6 h. Thereaction mixture was evaporated in vacuo, and the residue partitionedbetween dichloromethane (20 mL) and water (3×20 mL). The organic layerwas separated and added to SiO₂, and eluted from 0-15% methanol in ethylacetate to give the title compound (0.013 g, 22%) as an oil.

Mass spectrum (API⁺): Found 489 (MH⁺). C₃₀H₄₀N₄O₂ requires 488.

¹H NMR (CDCl₃) δ: 1.09 (6H, t, J=7 Hz), 1.58 (2H, m), 1.67 (1H, m), 1.74(2H, m), 2.36 (2H, m), 2.56 (2H, d, J=7 Hz), 2.65 (4H, q, J=7 Hz), 2.73(3H, s), 3.10 (2H, m), 3.14 (2H, s), 3.23 (2H, m), 4.41 (2H, m), 6.81(1H, d, J=7 Hz), 6.88 (1H, d, J=8 Hz), 7.23 (2H, m), 7.33 (1H, m), 7.46(1H, m), 7.55 (1H, m), 7.61 (1H, m), 8.40 (1H, d, J=8 Hz), 9.36 (1H,bs).

EXAMPLE 47N-(3-(1-(2-(2-Methylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)-2-pyrrolidin-1-ylacetamide(E47)

The title compound was prepared using methods analogous to Example 46.

Mass spectrum (API⁺): Found 487 (MH⁺). C₃₀H₃₈N₄O₂ requires 486.

¹H NMR (CDCl₃) δ: 1.54 (2H, m), 1.65 (1H, m), 1.73 (2H, m), 1.86 (4H,m), 2.34 (2H, m), 2.55 (2H, d, J=7 Hz), 2.71 (7H, m), 3.08 (2H, m), 3.20(2H, m), 3.28 (2H, s), 4.39 (2H, m), 6.80 (1H, d, J=8 Hz), 6.88 (1H, d,J=8 Hz), 7.24 (2H, m), 7.36 (1H, m), 7.44 (1H, m), 7.55 (1H, m), 7.61(1H, m), 8.40 (1H, d, J=8 Hz), 9.07 (1H, bs).

EXAMPLE 483-(1-(2-(2-Methylquinazolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)nitrobenzene(E48)

A mixture of 5-(2-methanesulfonyloxyethyl)-2-methylquinazoline (0.28 g,1.0 mmol), 4-(3-nitrobenzylidene)piperidine hydrochloride (0.25 g, 1.0mmol), and potassium carbonate (0.42 g, 3.0 mmol) inN,N-dimethylformamide (7 mL) was stirred at 100° C. for 2 h. Thereaction mixture was cooled, partitioned between water (4×10 mL) anddichloromethane (10 mL). The organic layer was added to SiO₂ and elutingfrom 0-5% methanol in ethyl acetate gave the title compound (0.17 g,42%) as a brown solid.

Mass spectrum (API⁺): Found 405 (MH⁺). C₂₃H₂₄N₄O₃ requires 404.

¹H NMR (CDCl₃) δ: 2.47 (2H, m), 2.53 (2H, m), 2.66 (2H, m), 2.78 (2H,m), 2.88 (3H, m), 3.01 (2H, m), 4.34 (2H, m), 6.33 (1H, s), 6.87 (1H, d,J=8 Hz), 7.49 (3H, m), 7.75 (1H, t, J=8 Hz), 8.04 (2H, m), 9.64 (1H, s).

EXAMPLE 49N-(3-(1-2-(2-Methylquinazolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)methanesulfonamide(E49)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 455 (MH⁺). C₂₄H₃₀N₄O₃S requires 454.

¹H NMR (CDCl₃) δ: 1.33 (2H, m), 1.55 (1H, m), 1.64 (2H, m), 2.16 (2H,m), 2.54 (2H, d, J=7 Hz), 2.88 (3H, s), 2.94 (2H, m), 3.02 (5H, m), 4.30(2H, m), 6.85 (1H, d, J=8 Hz), 6.97 (1H, m), 7.01 (1H, s), 7.05 (1H, m),7.25 (1H, m), 7.49 (1H, d, J=8 Hz), 7.74 (1H, t, J=8 Hz), 9.63 (1H, s).

EXAMPLE 50N-Methyl-N-(3-{4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}phenyl)acetamide(E50)

The title compound was prepared fromN-(3-{4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}phenyl)acetamidein a similar manner to Example 4.

Mass spectrum (API⁺): Found 433 (MH⁺). C₂₆H₃₂N₄O₂ requires 432.

EXAMPLE 51N-Ethyl-N-(3-{4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}phenyl)acetamide(ES1)

The title compound was prepared fromN-(3-{4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}phenyl)acetamidein a similar manner to Example 4.

Mass spectrum (API⁺): Found 447 (MH⁺). C₂₇H₃₄N₄O₂ requires 446.

¹H NMR (CDCl₃) δ: 1.11 (3H, t J 7), 1.82 (3H, s), 2.47-2.51 (4H, br),2.70 (4H, br s), 2.73 (3H, s), 2.97 (2H, t J 6), 3.55 (2H, s), 3.74 (2H,q J 7), 4.29 (2H, t J 6), 6.79 (1H, dd J 7 and 1), 7.02-7.06 (1H, m),7.16 (1H, s), 7.23-7.39 (3H, m), 7.51-7.62 (2H, m), 8.42 (1H, d J 9).

EXAMPLE 525-{2-[4-(4-Methoxy-3-nitrobenzylidene)piperidin-1-yl]ethoxy}-2-methylquinoline(E52)

The title compound was prepared using an analogous route andintermediates to that used to prepare Example 1.

Mass spectrum (API⁺): Found 434 (MH⁺). C₂₅H₂₇N₃O₄ requires 433.

¹H NMR (CDCl₃) δ: 2.43 (2H, t J 5), 2.51 (2H, t J 5), 2.64 (2H, t J 5),2.73-2.76 (5H, m), 2.99 (2H, t J 6), 3.95 (3H, s), 4.30 (2H, t J 6),6.80 (1H, d J 1), 7.02 (1H, t J 9), 7.26 (1H, t J 2), 7.34 (1H, dd J 9and 2), 7.54-7.62 (2H, m), 7.67 (2H, t J 2), 8.44 (1H, d J 9).

EXAMPLE 535-{2-[4-(3-Amino-4-methoxybenzyl)piperidin-1-yl]ethoxy})-2-methylquinoline(E53)

The title compound was prepared from5-{2-[4-(4-methoxy-3-nitrobenzylidene)piperidin-1-yl]ethoxy}-2-methylquinolinefollowing the method of Example 2.

Mass spectrum (API⁺): Found 406 (MH⁺). C₂₅H₃₁N₃O₂ requires 405.

¹H NMR (CDCl₃) δ: 1.25-1.35 (2H, m), 1.46-1.49 (1H, m), 1.65-1.68 (2H,m), 2.09-2.15 (2H, m), 2.39 (2H, d J 7), 2.72 (3H, s), 2.91 (2H, t J 6),3.01-3.04 (2H, m), 3.81 (3H, s), 4.26 (2H, t J 6), 6.47-6.51 (2H, m),6.68-6.70 (1H, m), 6.77-6.79 (1H, m), 7.22-7.26 (1H, m), 7.52-7.60 (2H,m), 8.42 (1H, d J 9).

EXAMPLE 54N-(2-Methoxy-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)methanesulfonamide(E54)

The title compound was prepared from5-{2-[4-(3-amino-4-methoxybenzyl)piperidin-1-yl]ethoxy}-2-methylquinolinefollowing the method of Example 3.

Mass spectrum (API⁺): Found 484 (MH⁺). C₂₆H₃₃N₃O₄S requires 483.

¹H NMR (CDCl₃) δ: 1.26-1.37 (2H, m), 1.49-1.53 (1H, m), 1.62-1.66 (2H,m), 2.10-2.16 (2H, m), 2.48 (2H, d J 7), 2.72 (3H, s), 2.87-2.94 (5H,m), 3.01-3.03 (2H, m), 3.84 (3H, s), 4.26 (2H, t J 6), 6.80 (2H, t J 9),6.89-6.91 (1H, m), 7.23-7.27 (2H, m), 7.32 (1H, d J 2), 7.52-7.60 (2H),8.43 (1H, d J 9).

EXAMPLE 552-Methyl-5-{2-[4-(3-nitrophenoxy)piperidin-1-yl]ethoxy}quinoline (E55)

The title compound was prepared from 5-(2-bromoethoxy)-2-methylquinolineand 4-(3-nitrophenoxy)piperidine using the method of Example 1.

Mass spectrum (API⁺): Found 408 (MH⁺). C₂₃H₂₅N₃O₄ requires 407.

¹H NMR (250 MHz, CDCl₃) δ: 1.84-1.95 (2H, m), 2.02-2.10 (2H, m),2.53-2.62 (2H, m), 2.73 (3H, s), 2.89-2.97 (2H, m), 3.00 (2H, t), 4.30(2H, t), 4.40-4.50 (2H, m), 6.82 (1H, dd), 7.20-7.29 (2H, m), 7.41 (1H,t), 7.53-7.64 (2H, m), 7.74 (1H, m), 7.78-7.82 (1H, m), 8.45 (1H, d).

EXAMPLE 56N-(3-{1-[2-(2-Methylquinolin-5-yloxy)ethyl]piperidin-4-yloxy}phenyl)methanesulphonamide(E56)

The title compound was prepared from5-{2-[4-(3-aminophenoxy)piperidin-1-yl]ethoxy}-2-methylquinoline usingthe method of Example 3.

Mass spectrum (API⁺): Found 456 (MH⁺). C₂₄H₂₉N₃O₄S requires 455.

¹H NMR (250 MHz, CDCl₃) δ: 1.80-1.90 (2H, m), 1.97-2.06 (2H, m),2.49-2.58 (2H, m), 2.73 (3H, s), 2.86-2.95 (2H, m), 2.97 (2H, t), 3.01(3H, s), 4.28 (2H, t), 4.30-4.39 (1H, m), 6.71-6.77 (2H, m), 6.80-6.86(2H, m), 7.19-7.28 (2H, m), 7.52-7.63 (2H, m), 8.45 (1H, d).

EXAMPLE 57N-(2-Chloro-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-yloxy}phenyl)methanesulphonamide(E57)

The title compound was prepared from5-{2-[4-(3-amino-4-chlorophenoxy)piperidin-1-yl]ethoxy}-2-methylquinolineusing the method of Example 3.

Mass spectrum (API⁺): Found 490 (MH⁺). C₂₄H₂₈ ³⁵ClN₃O₄S requires 489.

¹H NMR (250 MHz, CDCl₃) 8:1.80-1.91 (2H, m), 1.98-2.08 (2H, m),2.51-2.60 (2H, m), 2.73 (3H, s), 2.86-2.97 (2H, m), 2.99 (2H, t), 3.00(3H, s), 4.29 (2H, t), 4.304.39 (1H, m), 6.69 (1H, dd), 6.81 (1H, d),7.20-7.30 (3H, m), 7.52-7.63 (2H, m), 8.45 (1H, d).

EXAMPLE 585-(2-(4-(3-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene)piperidin-1-y)ethoxy)-2-methylquinoline(E58)

A mixture of cesium carbonate (0.28 g, 0.86 mmol), palladium (II)acetate (0.013 g, 0.057 mmol), and BINAP (0.053 g, 0.086 mmol) in1,4-dioxane (5 mL) was sonicated at 20° C. under argon for 0.5 h. Tothis mixture was added3-(1-(2-(2-methylquinolin-5-yloxy)ethyl)piperidin-4-ylidenemethyl)bromobenzene(0.25 g, 0.57 mmol) and cis-2,6-dimethylpiperazine (0.2 g, 1.75 mmol)and the mixture stirred at reflux for 72 h. The mixture was cooled to20° C. and filtered through celite and the filtrate was evaporated invacuo. Chromatography of the residue on SiO₂ eluting from 0-15% methanolin ethyl acetate and 2% 0.880 ammonia in 15% methanol in ethyl acetategave the title compound (0.12 g, 45%) as an oil.

Mass spectrum (API⁺): Found 471 (MH⁺). C₃₀H₃₈N₄O requires 470.

¹H NMR (CDCl₃)δ: 1.13 (6H, m), 2.29 (2H, m), 2.42 (2H, m), 2.57 (2H, m),2.62 (2H, m), 2.73 (5H, m), 2.88-3.06 (5H, m), 3.50 (2H, m), 4.30 (2H,m), 6.28 (1H, s), 6.70 (1H, d, J=7 Hz), 6.78 (3H, m), 7.22 (2H, m), 7.57(2H, m), 8.44 (1H, d, J=9 Hz).

EXAMPLE 592-Methyl-5-(2-(4-(3-(4-methylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)quinoline(E59)

The title compound was prepared in a similar manner to Example 58.

Mass spectrum (API⁺): Found 457 (MH⁺). C₂₉H₃₆N₄O requires 456.

¹H NMR (CDCl₃) δ: 2.35 (3H, s), 2.42 (2H, m), 2.57 (6H, m), 2.62 (2H,m), 2.73 (5H, m), 2.97 (2H, m), 3.20 (4H, m), 4.30 (2H, m), 6.27 (1H,s), 6.72 (1H, d, J=8 Hz), 6.79 (3H, m), 7.22 (2H, m), 7.57 (2H, m), 8.44(1H, d, J=9 Hz).

EXAMPLE 605-(2-(4-(3-(cis-3,5-Dimethylpiperazin-1-yl)benzyl)piperidin-1-yl)ethoxy)-2-methylquinoline(E60)

A mixture of5-(2-(4-(3-(cis-3,5-dimethylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)-2-methylquinoline(0.1 g, 0.21 mmol) and 10% palladium on charcoal (paste) (0.13 g) inmethanol (10 mL) was stirred at 20° C. under an atmosphere of hydrogen(1 atm) for 3 h. The reaction mixture was filtered through celite andthe filtrate evaporated in vacuo to give the title compound (0.081 g,82%) as an oil.

Mass spectrum (API⁺): Found 473 (MH⁺). C₃₀H₄₀N₄O requires 472.

¹H NMR (CDCl₃) δ: 1.14 (6H, m), 1.34 (2H, m), 1.57 (1H, m), 1.68 (2H,m), 2.13 (2H, m), 2.27 (2H, m), 2.50 (2H, d, J=7 Hz), 2.72 (3H, s), 2.91(4H, m), 3.04 (3H, m), 3.50 (2H, m), 4.27 (2H, m), 6.64 (1H, d, J=7 Hz),6.70 (1H, s), 6.77 (2H, m), 7.16 (1H, t, J=8 Hz), 7.24 (1H, d, J=9 Hz),7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 612-Methyl-5-(2-(4-(3-(4-methylpiperazin-1-yl)benzyl)piperidin-1-yl)ethoxy)quinoline(E61)

The title compound was prepared from2-methyl-5-(2-(4-(3-(4-methylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)quinolinein a similar manner to Example 60.

Mass spectrum (API⁺): Found 459 (MH⁺). C₂₉H₃₈N₄O requires 458.

¹H NMR (CDCl₃) δ: 1.33 (2H, m), 1.53 (1H, m), 1.67 (2H, m), 2.13 (2H,m), 2.35 (3H, s), 2.49 (2H, d, J=7 Hz), 2.57 (4H, m), 2.72 (3H, s), 2.92(2H, m), 3.02 (2H, m), 3.20 (4H, m), 4.27 (2H, m), 6.65 (1H, d, J=7 Hz),6.72 (1H, s), 6.77 (2H, m), 7.16 (1H, t, J=8 Hz), 7.24 (1H, d, J=9 Hz),7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 622-Methyl-542-(4-(3-((R)-3-methylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)quinoline(E62)

The title compound was prepared in a similar manner to Example 58.

Mass spectrum (API⁺): Found 457 (MH⁺). C₂₉H₃₆N₄O require 456.

¹H NMR (CDCl₃) δ: 1.12 (3H, d, J=6 Hz), 2.34 (1H, m), 2.42 (2H, m), 2.56(2H, m), 2.62 (2H, m), 2.73 (7H, m), 2.97 (2H, m), 3.07 (3H, m), 3.50(2H, m), 4.29 (2H, m), 6.28 (1H, s), 6.71 (1H, d, J=8 Hz), 6.78 (3H, m),7.22 (2H, m), 7.57 (2H, m), 8.44 (1H, d, J=8 Hz).

EXAMPLE 632-Methyl-5-{2-[4-(3-morpholin-4-yl)benzylidene)piperidin-1-yl]ethoxy}quinoline(E63)

The title compound was prepared in a similar manner to Example 58.

Mass spectrum (API⁺): Found 444 (MH⁺). C₂₈H₃₃N₃O₂ requires 443.

¹H NMR (CDCl₃) δ: 2.42 (2H, m), 2.56 (2H, m), 2.63 (2H, m), 2.73 (5H,m), 2.97 (2H, m), 3.15 (4H, m), 4.12 (4H, m), 4.30 (2H, m), 6.28 (1H,s), 6.77 (4H, m), 7.23 (2H, m), 7.57 (2H, m), 8.44 (1H, d, J=8 Hz).

EXAMPLE 645-(2-{4-[3-((2S,5R)-2,5-Dimethylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)-2-methylquinoline(E64)

The title compound was prepared in a similar manner to Example 58.

Mass spectrum (API⁺): Found 471 (MH⁺). C₃₀H₃₈N₄O requires 470.

¹H NMR (CDCl₃) δ: 0.91 (3H, m), 1.05 (3H, m), 2.41 (4H, m), 2.56 (2H,m), 2.64 (2H, m), 2.70 (5H, m), 2.95 (4H, m), 3.07 (3H, m), 4.30 (2H,m), 6.27 (1H, m), 6.81 (1H, m), 6.94 (2H, m), 7.25 (2H, m), 7.57 (2H,m), 8.45 (2H, d, J=9 Hz).

EXAMPLE 652-Methyl-5-(2-(4-(3-((S)-3-methylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)quinoline(E65)

The title compound was prepared in a similar manner to Example 58.

Mass spectrum (API⁺): Found 457 (MH⁺). C₂₉H₃₆N₄O requires 456.

¹H NMR (CDCl₃) 5:1.12 (3H, m), 2.35 (1H, m), 2.42 (2H, m), 2.56 (2H, m),2.62 (2H, m), 2.73 (7H, m), 2.97 (2H, m), 3.07 (3H, m), 3.50 (2H, m),4.30 (2H, m), 6.28 (1H, s), 6.71 (1H, d, J=8 Hz), 6.79 (3H, m), 7.23(2H, m), 7.57 (2H, m), 8.44 (1H, d, J=9 Hz).

EXAMPLE 662-Methyl-5-(2-(4-(3-((R)-3-methylpiperazin-1-yl)benzyl)piperidin-1-yl)ethoxy)quinoline(E66)

The title compound was prepared from2-methyl-5-(2-(4-(3-((R)-3-methylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)quinolinein a similar manner to Example 60.

Mass spectrum (API⁺): Found 459 (MH⁺). C₂₉H₃₈N₄O requires 458.

¹H NMR (CDCl₃) δ: 1.13 (3H, d, J=6 Hz), 1.33 (2H, m), 1.55 (1H, m), 1.67(2H, m), 2.13 (2H, m), 2.33 (1H, m), 2.50 (2H, m), 2.69 (2H, m), 2.72(3H, s), 2.92 (2H, m), 2.96-3.09 (5H, m), 3.50 (2H, m), 4.27 (2H, m),6.65 (1H, d, J=7 Hz), 6.71 (1H, s), 6.77 (2H, m), 7.16 (1H, t, J=8 Hz),7.24 (1H, d, J=9 Hz), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 672-Methyl-5-{2-[4-(3-morpholin-4-ylbenzyl)piperidin-1-yl]ethoxy}quinoline(E67)

The title compound was prepared from2-methyl-5{2-[4-(3-morpholin-4-ylbenzylidene)piperidin-1-yl]ethoxy}quinolinein a similar manner to Example 60.

Mass spectrum (API⁺): Found 446 (MH⁺). C₂₈H₃₅N₃O₂ requires 445.

¹H NMR (CDCl₃) δ: 1.33 (2H, m), 1.54 (1H, m), 1.67 (2H, m), 2.13 (2H,m), 2.50 (2H, d, J=7 Hz), 2.72 (3H, s), 2.92 (2H, m), 3.03 (2H, m), 3.14(4H, m), 3.85 (4H, m), 4.26 (2H, m), 6.68 (2H, m), 6.74 (1H, dd, J=8, 2Hz), 6.78 (1H, d, J=7 Hz), 7.18 (1H, t, J=8 Hz), 7.23 (1H, d, J=8 Hz),7.56 (2H, m), 8.42 (1H, d, J=8 Hz).

EXAMPLE 685-(2-{4-[3-((2S,5R)-2,5-Dimethylpiperazin-1-yl)benzyl]piperidin-1-yl}ethoxy)-2-methylquinoline(E68)

The title compound was prepared from5-(2-{4-[3-((2S,5R)-2,5-dimethylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)-2-methylquinolinein a similar manner to Example 60.

Mass spectrum (API⁺): Found 473 (MH⁺). C₃₀H₄₀N₄O requires 472.

¹H NMR (CDCl₃) δ: 0.90 (3H, m), 1.08 (3H, m), 1.34 (2H, m), 1.55 (1H,m), 1.66 (2H, m), 2.14 (2H, m), 2.50 (4H, m), 2.71 (5H, m), 2.98 (2H,m), 2.98-3.11 (5H, m), 4.27 (2H, m), 6.79 (1H, dd, J=8, 1 Hz), 6.87 (2H,m), 6.95 (1H, m), 7.22 (2H, m), 7.56 (2H, m), 8.43 (1H, d, J=8 Hz).

EXAMPLE 695-(2-{4-[3-((2R,6S)-2,6-Dimethylmorpholin-4-yl)benzyl]piperidin-1-yl}ethoxy)-2-methylquinoline(E69)

The title compound was prepared in a similar manner to Example 60.

Mass spectrum (API⁺): Found 474 (MH⁺). C₃₀H₃₉N₃O₂ requires 473.

¹H NMR (CDCl₃)δ: 1.26 (6H, m), 1.34 (2H, m), 1.54 (1H, m), 1.67 (2H, m),2.14 (2H, m), 2.40 (2H, m), 2.50 (2H, d, J=7 Hz), 2.72 (3H, s), 2.91(2H, m), 3.04 (2H, m), 3.44 (2H, d, J=11 Hz), 3.80 (2H, m), 4.27 (2H,m), 6.67 (2H, m), 6.74 (1H, dd, J=8, 2 Hz), 6.79 (1H, d, J=7 Hz), 7.17(1H, t, J=8 Hz), 7.23 (1H, d, J=9 Hz), 7.56 (2H, m), 8.42 (1H, d, J=9Hz).

EXAMPLE 702-Methyl-5-{2-[4-(3-piperidin-1-ylbenzyl)piperidin-1-yl]ethoxy}quinoline(E70)

The title compound was prepared from2-methyl-5-{2-[4(3-piperidin-1-ylbenzylidene)piperidin-1-yl]ethoxy}quinolinein a similar manner to Example 60.

Mass spectrum (API⁺): Found 444 (MH⁺). C₂₉H₃₇N₃O requires 443.

¹H NMR (CDCl₃) δ: 1.33 (2H, m), 1.57 (3H, m), 1.70 (6H, m), 2.13 (2H,m), 2.49 (2H, d, J=7 Hz), 2.72 (3H, s), 2.92 (2H, m), 3.03 (2H, m), 3.14(4H, m), 4.27 (2H, m), 6.61 (1H, d, J=7 Hz), 6.76 (3H, m), 7.14 (1H, t,J=8 Hz), 7.24 (1H, d, J=9 Hz), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 712-Methyl-5-(2-{4-[3-((S)-3-methylpiperazin-1-yl)benzyl]piperidin-1-yl}ethoxy)quinoline(E71)

The title compound was prepared from2-methyl-5-(2-(4-(3-((S)-3-methylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)quinolinein a similar manner to Example 60.

Mass spectrum (API⁺): Found 459 (MH⁺). C₂₉H₃₈N₄O requires 458.

¹H NMR (CDCl₃)δ: 1.13 (3H, m), 1.34 (2H, m), 1.55 (1H, m), 1.67 (2H, m),2.16 (2H, m), 2.34 (1H, m), 2.50 (2H, d, J=7 Hz), 2.72 (5H, m), 2.92(2H, m), 2.98-3.09 (5H, m), 3.48 (2H, m), 4.27 (2H, m), 6.65 (1H, d, J=7Hz), 6.71 (1H, s), 6.77 (2H, m), 7.16 (1H, t, J=8 Hz), 7.24 (1H, d, J=9Hz), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 722-Methyl-5-(2-{4-[3-(4-methyl[1,4]diazepan-1-yl)benzyl]piperidin-1-yl}ethoxy)quinoline(E72)

The title compound was prepared in a similar manner to Example 60.

Mass spectrum (API⁺): Found 473 (MH⁺). C₃₀H₄₀N₄O requires 472.

¹H NMR (CDCl₃) δ: 1.34 (2H, m), 1.55 (1H, m), 1.69 (2H, m), 2.14 (2H,m), 2.38 (3H, s), 2.48 (2H, d, J=7 Hz), 2.57 (4H, m), 2.72 (5H, m), 2.93(2H, m), 3.03 (2H, m), 3.47 (2H, m), 3.56 (2H, m), 4.27 (2H, m), 6.47(2H, m), 6.53 (1H, m), 6.79 (1H, d, J=7 Hz), 7.11 (1H, t, J=8 Hz), 7.24(1H, m), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 732-Methyl-5-(2-(4-(3-pyrrolidin-1-ylbenzyl)piperidin-1-yl)ethoxy)quinoline(E73)

The title compound was prepared in a similar manner to Example 60.

Mass spectrum (API⁺): Found 430 (MH⁺). C₂₈H₃₅N₃O requires 429.

¹H NMR (CDCl₃) δ: 1.36 (2H, m), 1.54 (1H, m), 1.68 (2H, m), 1.74 (4H,m), 1.98 (2H, m), 2.13 (2H, m), 2.54 (2H, d, J=7 Hz), 2.72 (3H, s), 2.92(2H, m), 3.03 (2H, m), 3.27 (2H, m), 4.27 (2H, m), 6.79 (1H, m), 7.14(1H, m), 7.26 (4H, m), 7.56 (2H, m), 8.43 (1H, d, J=9 Hz).

EXAMPLE 742-Methyl-5-{2-[4-(3-piperidin-1-ylbenzylidene)piperidin-1-yl]ethoxy}quinoline(E74)

The title compound was prepared in a similar manner to Example 58.

Mass spectrum (API⁺): Found 442 (MH⁺). C₂₉H₃₅N₃O requires 441.

¹H NMR (CDCl₃) δ: 1.57 (2H, m), 1.70 (4H, m), 2.42 (2H, m), 2.58 (2H,m), 2.62 (2H, m), 2.73 (5H, m), 2.97 (2H, m), 3.14 (4H, m), 4.30 (2H,m), 6.27 (1H, s), 6.68 (1H, d, J=8 Hz), 6.79 (3H, m), 7.18 (1H, t, J=8Hz), 7.25 (1H, m), 7.57 (2H, m), 8.44 (1H, d, J=9 Hz).

EXAMPLE 752-Methyl-5-(2-(4-(3-piperidin-1-ylbenzylidene)piperidin-1-yl)ethoxy)quinazoline(E75)

The title compound was prepared in a similar manner to Example 58 from5-(2-(4-(3-bromobenzylidene)piperidin-1-yl)ethoxy)-2-methylquinazoline.

Mass spectrum (API⁺): Found 443 (MH⁺). C₂₈H₃₄N₄O requires 442.

¹H NMR (CDCl₃) δ: 1.57 (2H, m), 1.70 (4H, m), 2.42 (2H, m), 2.54 (2H,m), 2.58 (2H, m), 2.62 (2H, m), 2.88 (3H, s), 2.99 (2H, m), 3.14 (4H,m), 4.33 (2H, m), 6.28 (1H, s), 6.68 (1H, d, J=7 Hz), 6.79 (2H, m), 6.87(1H, d, J=8 Hz), 7.19 (1H, m), 7.50 (1H, d, J=9 Hz), 7.77 (1H, t, J=8Hz), 9.65 (1H, s).

EXAMPLE 762-Methyl-5-(2-(4-(3-piperidin-1-ylbenzyl)piperidin-1-yl)ethoxy)quinazoline(E76)

The title compound was prepared from2-methyl-5-(2-(4-(3-piperidin-1-ylbenzylidene)piperidin-1-yl)ethoxy)quinazolinein a similar manner to Example 60.

Mass spectrum (API⁺): Found 445 (MH⁺). C₂₈H₃₆N₄O requires 444.

¹H NMR (CDCl₃) δ: 1.33 (2H, m), 1.57 (3H, m), 1.70 (6H, m), 2.14 (2H,m), 2.48 (2H, d, J=7 Hz), 2.88 (3H, s), 2.93 (2H, m), 3.02 (2H, m), 3.14(4H, m), 4.30 (2H, m), 6.61 (1H, d, J=7 Hz), 6.72 (1H, s), 6.76 (1H, dd,J=8, 2 Hz), 6.85 (1H, d, J=8 Hz), 7.14 (1H, t, J=8 Hz), 7.48 (1H, d, J=8Hz), 7.73 (1H, t, J=8 Hz), 9.63 (1H, s).

EXAMPLE 77N-(3-{4-[2-(2-Methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}phenyl)-acetamide(E77)

A mixture of 2-methyl-5-(2-piperazin-1-ylethoxy)quinoline (0.04 g, 0.15mmol) and 3-acetamidobenzaldehyde (0.024 g, 0.15 mmol) in1,2-dichloroethane (5 mL) was treated with sodium triacetoxyborohydride(47 m g, 0.22 mmol) and stirred at 20° C. under an atmosphere of argonfor 24 h. The mixture was then treated with saturated aqueous NaHCO₃ (20mL) and the organic layer separated and purified directly bychromatography on silica (ethyl acetate to 10% methanol/ethyl acetate),to afford the title compound (0.034 g, 55%) as a solid.

Mass spectrum (API⁺): Found 419 (MH⁺). C₂₅H₃₀N₄O₂ requires 418.

¹H NMR (CDCl₃) δ: 2.15 (3H, s), 2.41-2.50 (4H, m), 2.67 (4H, br), 2.72(3H, s), 2.95 (2H, t J 6), 3.48 (2H, s), 4.27 (2H, t J 6), 6.78 (1H, ddJ 7 and 1), 7.05 (1H, d J 8), 7.22-7.28 (2H, m), 7.43-7.61 (4H, m), 8.42(1H, d J 9).

The examples of Table 1 were prepared in a similar manner to ExampleE77. TABLE 1

Example R7 R2 Mass Spectrum (APl⁺) E78 NO₂ OMe Found requires 437 436.(MH⁺). C₂₄H₂₈N₄O₄ E79 NO₂ H Found requires 407 406. (MH⁺). C₂₃H₂₆N₄O₃E80 NO₂ F Found requires 425 424. (MH⁺). C₂₃H₂₅FN₄O₃ E81 NO₂ Me Foundrequires 421 420. (MH⁺). C₂₄H₂₈N₄O₃ E82 NO₂ Cl Found requires 441 440.(MH⁺). C₂₃H₂₅ClN₄O₃ E83 NHSO₂Me H Found requires 455 454. (MH⁺).C₂₄H₃₀N₄O₃S E84 4-methyl-1- piperazinyl H Found requires 460 459. (MH⁺).C₂₈H₃₇N₅O E85 1-imidazolinyl H Found requires 428 427. (MH⁺). C₂₆H₂₉N₅O

EXAMPLE 862-Amino-4-{4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazin-1-ylmethyl}phenol(E86)

5-{2-[4-(4-Methoxy-3-nitrobenzyl)piperazin-1-ylmethyl]ethoxy}-2-methylquinoline(0.169 g, 0.4 mmol) was dissolved in methanol (20 mL) and treated with10% palladium on carbon (0.169 g) and ammonium formate (0.126 g, 2.0mmol) and the resulting mixture stirred at ambient temperature for 2 hbefore being filtered through Kieselguhr. The filtrate was evaporated todryness under reduced pressure and the residue partitioned between ethylacetate and saturated NaHCO₃ aq. The phases were separated and theorganic phase washed with saturated brine, dried (MgSO₄) and evaporatedto dryness under reduced pressure. Chromatography of the residue onSiO₂, eluting with 10% 0.880 NH₃/MeOH in dichloromethane (0-10%gradient), gave the title compound (0.099 g, 63%) as a brown gum.

¹H NMR (CDCl₃) δ: 2.52 and 2.70 (each 4H, 2br m), 2.72 (3H, s), 2.96(2H, t), 3.38 (2H, s), 4.27 (2H, t), 6.48 (1H, dd), 6.55 (1H, d), 6.70(1H, d), 6.77 (1H, d), 7.23 (1H, d) 7.53 (1H, t), 7.61 (1H, d), 8.43(1H, d).

EXAMPLE 87 N-(4-Fluoro-2-methoxy-5-{1[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)methanesulfonamide(E87)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 502 (MH⁺). C₂₆H₃₂FN₃O₄S requires 501.

¹H NMR (CDCl₃) δ: 1.30-1.45 (2H, m), 1.50-1.70 (3H, m), 2.10-2.20 (2H,m), 2.53 (2H, d, J=8 Hz), 2.73 (3H, s), 2.85-2.95 (5H, m), 3.00-3.05(2H, m), 3.85 (3H, s), 4.26 (2H, t, J=6 Hz), 6.51 (1H, br. s), 6.63 (1H,d, J=11 Hz), 6.79 (1H, d, J=8 Hz), 7.23 (1H, d, J=8 Hz), 7.30 (1H, d,J=8 Hz), 7.50-7.70 (2H, m), 8.43 (1H, d, J=8 Hz).

EXAMPLE 88N-(4-Fluoro-2-methoxy-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)-2-propanesulfonamide(E88)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 530 (MH⁺). C₂₈H₃₆FN₃O₄S requires 529.

¹H NMR (CDCl₃) δ: 1.35 (6H, d, J=7 Hz), 1.48-1.58 (1H, m), 1.60-1.70(4H, m), 2.10-2.20 (2H, m), 2.52 (2H, d, J=8 Hz), 2.73 (3H, s), 2.92(2H, t, J=6 Hz), 2.95-3.05 (2H, m), 3.10-3.20 (1H, m), 3.85 (3H, s),4.26 (2H, t, J=6 Hz), 6.50 (1H, br. s), 6.60 (1H, d, J=11 Hz), 6.79 (1H,d, J=8 Hz), 7.26 (1H, d, J=8 Hz), 7.36 (1H, d, J=8 Hz), 7.50-7.60 (2H,m), 8.43 (1H, d, J=8 Hz).

EXAMPLE 891-(4-Fluoro-2-methoxy-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)pyrrolidin-2-one(E89)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 5.

Mass spectrum (API⁺): Found 492 (MH⁺). C₂₉H₃₄FN₃O₃ requires 491.

¹H NMR (CDCl₃) δ: 1.30-1.48 (2H, m), 1.50-1.80 (3H, m), 2.10-2.25 (4H,m), 2.45-2.60 (4H, m), 2.73 (3H, s), 2.93 (2H, t, J=6 Hz), 3.02-3.06(2H, m), 3.71 (2H, t, J=4 Hz), 3.79 (3H, s), 4.28 (2H, t, J=6 Hz), 6.64(1H, d, J=12 Hz), 6.79 (1H, d, J=8 Hz), 7.00 (1H, d, J=8 Hz), 7.25 (1H,d, J=10 Hz), 7.50-7.60 (2H, m), 8.43 (1H, d, J=8 Hz).

EXAMPLE 90N-(3-Fluoro-2-methoxy-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)-methanesulfonamide(E90)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 502 (MH⁺). C₂₆H₃₂FN₃O₄S requires 501.

¹H NMR (CDCl₃) δ: 1.30-1.42 (2H, m), 1.45-1.60 (1H, m), 1.60-1.70 (2H,m), 2.17 (2H, t, J=12 Hz), 2.48 (2H, d, J=8 Hz), 2.72 (3H, s), 2.95 (2H,t, J=6 Hz), 3.00 (3H, s), 3.02-3.09 (2H, m), 3.97 (3H, s), 4.28 (2H, t,J=6 Hz), 6.66 (1H, d, J=11 Hz), 6.79 (1H, d, J=8 Hz), 7.10 (1H, s), 7.25(1H, d, J=8 Hz), 7.50-7.61 (2H, m), 8.43 (1H, d, J=8 Hz).

EXAMPLE 91N-(3-Fluoro-2-methoxy-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)-1-propanesulfonamide(E91)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 530 (MH⁺). C₂₈H₃₆FN₃O₄S requires 529.

¹H NMR (CDCl₃) δ: 1.01 (3H, t, J=8 Hz), 1.30-1.40 (2H, m), 1.48-1.58(1H, m), 1.60-1.70 (2H, m), 1.80-1.90 (2H, m), 2.10-2.20 (2H, m), 2.47(2H, d, J=7 Hz), 2.73 (3H, s), 2.93 (2H, t, J=6 Hz), 3.00-3.10 (4H, m),3.97 (3H, s), 4.28 (2H, t, J=6 Hz), 6.66 (1H, d, J=12 Hz), 6.80 (1H, d,J=8 Hz), 6.85 (1H, br, s), 7.11 (1H, s), 7.25 (1H, d, J=8 Hz), 7.50-7.70(2H, m), 8.43 (1H, d, J=8 Hz).

EXAMPLE 92N-(3-Fluoro-2-methoxy-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)-2-propanesulfonamide(E92)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 530 (MH⁺). C₂₈H₃₆FN₃O₄S requires 529.

¹H NMR (CDCl₃) δ: 1.25-1.40 (2H, m), 1.38 (6H, d, J=7 Hz), 1.45-1.60(1H, m), 1.60-1.72 (2H, m), 2.10-2.20 (2H, m), 2.46 (2H, d, J=8 Hz),2.73 (3H, s), 2.93 (2H, t, J=7 Hz), 3.00-3.10 (2H, m), 3.22-3.32 (1H,m), 3.97 (3H, s), 4.28 (2H, t, J=6 Hz), 6.63 (1H, d, J=12 Hz), 6.70-6.90(2H, m), 7.15 (1H, s), 7.25 (1H, d, J=8 Hz), 7.50-7.70 (2H, m), 8.43(1H, d, J=8 Hz).

EXAMPLE 935-(2-{4-[3-(1,1-Dioxo-1l⁶-isothiazolidin-2-yl)-5-fluoro-4-methoxybenzyl]piperidin-1-yl}ethoxy)-2-methylquinoline(E93)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 5.

Mass spectrum (API⁺): Found 529 (MH⁺). C₂₈H₃₄FN₃O₄S requires 528.

¹H NMR (CDCl₃) δ: 1.30-1.42 (2H, m), 1.45-1.50 (1H, m), 1.63-1.72 (2H,m), 2.10-2.25 (2H, m), 2.42-2.60 (4H, m), 2.73 (3H, s), 2.96 (2H, t, J=6Hz), 3.02-3.12 (2H, m), 3.28 (2H, t, J=7 Hz), 3.79 (2H, t, J=8 Hz), 3.96(3H, s), 4.30 (2H, t, J=6 Hz), 6.80 (1H, d, J=7 Hz), 6.85 (1H, dd, J=8,2 Hz), 7.00 (1H, s), 7.25 (1H, d, J=8 Hz), 7.50-7.70 (2H, m), 8.43 (1H,d, J=8 Hz).

EXAMPLE 941-(3-Fluoro-2-methoxy-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)pyrrolidin-2-one(E94)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 5.

Mass spectrum (API⁺): Found 492 (MH⁺). C₂₉H₃₄FN₃O₃ requires 491.

¹H NMR (CDCl₃) δ: 1.30-1.48 (2H, m), 1.50-1.60 (1H, m), 1.64-1.76 (2H,m), 2.10-2.28 (4H, m), 2.48 (2H, d, J=7 Hz), 2.56 (2H, t, J=8 Hz), 2.73(3H, s), 2.98 (2H, t, J=6 Hz), 3.02-3.12 (2H, m), 3.76 (2H, t, J=8 Hz),3.90 (3H, s), 4.31 (2H, t, J=6 Hz), 6.70-6.90 (3H, m), 7.25 (1H, d, J=8Hz), 7.50-7.66 (2H, m), 8.42 (1H, d, J=8 Hz).

EXAMPLE 95N-(3-(1-(2-(2-Trifluoromethylquinolin-5-yloxy)ethyl)piperidin-4-ylmethyl)phenyl)methanesulfonamide(E95)

The title compound was prepared from5-(2-bromoethoxy)-2-trifluoromethylquinoline using analogous routes andintermediates to those used to prepare Example 3.

Mass spectrum (API⁺): Found 508 (MH⁺). C₂₅H₂₈F₃N₃O₃S requires 507.

¹H NMR (CDCl₃) δ: 1.25-1.38 (2H, m), 1.47-1.60 (1H, m), 1.60-1.70 (2H,m), 2.10-2.20 (2H, m), 2.55 (2H, d), 2.94 (2H, t), 3.00 (3H, s),3.02-3.08 (2H, m), 4.30 (2H, t), 6.92-6.99 (2H, m), 7.00-7.07 (2H, m),7.20-7.30 (1H, m), 7.66-7.73 (2H, m), 7.79 (1H, d), 8.74 (1H, d). NH notdiscernible.

EXAMPLE 965-(2-(4-(344-Methylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)-2-trifluoromethylquinoline(E96)

The title compound was prepared from5-(2-bromoethoxy)-2-trifluoromethylquinoline using analogous routes andintermediates to those used in Description 19 and Example 58.

Mass spectrum (API⁺): Found 511 (MH⁺). C₂₉H₃₃F₃N₄O requires 510.

¹H NMR (CDCl₃) δ: 2.34 (3H, s), 2.40-2.46 (2H, m), 2.52-2.59 (6H, m),2.60-2.66 (2H, m), 2.7-2.76 (2H, m), 2.99 (2H, t), 3.18-3.23 (4H, m),4.33 (2H, t), 6.28 (1H, s), 6.71 (1H, d), 6.73-6.80 (2H, m), 6.97 (1H,d), 7.20 (1H, t), 7.68-7.73 (2H, m), 7.80 (1H, d), 8.75 (1H, d).

EXAMPLE 975-(2-(4-(3-(4-Methylpiperazin-1-yl)benzyl)piperidin-1-yl)ethoxy)-2-trifluoromethylquinoline(E97)

The title compound was prepared from5-(2-(4-(3-(4-methylpiperazin-1-yl)benzylidene)piperidin-1-yl)ethoxy)-2-trifluoromethylquinolineusing an analogous method to Example 2.

Mass spectrum (API⁺): Found 513 (MH⁺). C₂₉H₃₅F₃N₄O requires 512.

¹H NMR (CDCl₃) δ: 1.22-1.30 (m, 2H), 1.49-1.60 (m, 1H), 1.68 (br d, 2H),2.14 (t, 2H), 2.35 (s, 3H), 2.49 (d, 2H), 2.57 (t, 4H), 2.94 (t, 2H),3.01 (br d, 2H), 3.20 (t, 4H), 4.30 (t, 2H), 6.65 (d, 1H), 6.72 (s, 1H),6.75 (dd, 1H), 6.95 (d, 1H), 7.72 (t, 1H), 7,67-7.71 (m, 2H), 7.79 (d,1H), 8.74 (d, 1H).

EXAMPLE 98N-(2-Methoxy-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)propane-1-sulfonamide(E98)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 512 (MH⁺). C₂₈H₃₇N₃O₄S requires 511.

¹H NMR (CDCl₃) δ: 1.01 (3H, t, J 7), 1.25-1.45 (2H, m), 1.55-1.70 (2H,m), 1.70-1.95 (3H, m), 2.10-2.23 (2H, m), 2.58 (2H, d, J 7), 2.72 (3H,s), 2.93 (2H, t, J 6), 3.00-3.16 (4H, m), 3.75 (3H, s), 4.27 (2H, t, J6), 6.79 (1H, d, J 7), 6.82 (1H, br. s), 6.89 (1H, dd, J 7 and 2), 7.03(1H, t, J 8), 7.24 (1H, d, J 8), 7.36 (1H, dd, J 8 and 2), 7.50-7.65(2H, m), 8.42 (1H, d, J 8).

EXAMPLE 99N-(2-Methoxy-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)propane-2-sulfonamide(E99)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 512 (MH⁺). C₂₈H₃₇N₃O₄S requires 511.

¹H NMR (CDCl₃) δ: 1.40 (6H, d, J7), 1.55-1.75 (5H, m), 2.10-2.25 (2H,m), 2.58 (2H, d, J 7), 2.73 (3H, s), 2.93 (2H, m), 3.01-3.08 (2H, m),3.36 (1H, m), 3.75 (3H, s), 4.28 (2H, t, J 6), 6.74 (1H, br. s), 6.79(1H, d, J 7), 6.87 (1H, dd, J 8 and 1), 7.01 (1H, t, J 8), 7.24 (1H, d,J 8), 7.36 (1H, dd, J 8 and 2), 7.50-7.65 (2H, m), 8.42 (1H, d, J 8).

EXAMPLE 100N-(2-Methoxy-3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)benzenesulfonamide(E100)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 3.

Mass spectrum (API⁺): Found 546 (MH⁺). C₃₁H₃₅N₃O₄S requires 545.

¹H NMR (CDCl₃) δ: 1.25 (2H, m), 1.51 (3H, m), 2.01 (2H, m), 2.46 (2H, d,J 7), 2.72 (3H, s), 2.91 (2H, t, J 6), 3.00 (2H, m), 3.45 (3H, s), 4.26(2H, t, J 6), 6.70-6.85 (2H, m), 6.97 (1H, t, J 8), 7.02 (1H, br. s),7.25 (1H, d, J 8), 7.42 (3H, m), 7.45-7.60 (3H, m), 7.83 (2H, dd, J 8and 1), 8.42 (1H, d, J8).

EXAMPLE 1015-(2-{4-[3-(1,1-Dioxo-1l⁶-isothiazolidin-2-yl)-2-methoxybenzyl]piperidin-1-yl}ethoxy)-2-methylquinoline(E101)

The title compound was prepared using analogous routes and intermediatesto those used to prepare Example 5.

¹H NMR (CDCl₃) δ: 1.35 (2H, m), 1.55-1.75 (7H, m), 2.17 (2H, m), 2.54(2H, d, J 7), 2.72 (3H, s), 2.94 (2H, t, J 6), 3.06 (2H, m), 3.73 (3H,s), 3.74 (2H, d, J 7), 4.29 (2H, t, J 6), 6.53 (1H, d, J 8), 6.61 (1H,d, J 8), 6.79 (1H, d, J 8), 6.84 (1H, t, J 8), 7.24 (1H, d, J 8),7.50-7.72 (2H, m), 8.42 (1H, d, J 8).

EXAMPLE 1021-Methyl-4-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)piperazin-2-one(E102)

The title compound was prepared from5-(2-[4-(3-bromobenzylidene)piperidin-1-yl]ethoxy)-2 methylquinoline ina manner similar to Example 58.

Mass spectrum (API⁺): Found 471 (MH⁺). C₂₉H₃₄N₄O₂ requires 470.

¹H NMR (CDCl₃) δ: 2.43 (2H, m), 2.56 (2H, m)_(m 2.64) (2H, m), 2.74 (5H,m), 2.98 (6H, m), 3.46 (3H s), 3.87 (2H, s), 4.31 (2H, m), 6.27 (1H,bs), 6.71-6.83 (4H, m), 7.24 (2H, m), 7.57 (2H, m), 8.4 (1H, d J 9).

EXAMPLE 1031-Methyl-4-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)piperazin-2-one(E103)

The title compound was prepared from1-methyl-4-(3-{1-[2-(2-methylquinolin-5yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)piperazin-2-one in a mannersimilar to Example 60.

Mass spectrum (API⁺): Found 473 (MH⁺). C₂₉H₃₆N₄O₂ requires 472.

¹H NMR (CDCl₃) δ: 1.39 (2H, m), 1.53 (1H, m), 1.67 (2H, m), 1.87 (2H,m), 2.51 (2H, d J 7), 2.7 (3H, s), 2.95-3.11 (8H, m), 3.46 (3H, s), 3.87(2H, s), 4.29 (2H, m), 6.67 (1H, m), 6.72 (1H, m), 6.7 (1H, m),7.16-7.26 (2H, m), 7.50-7.63 (3H, m), 8.42 (1H, d J 9).

EXAMPLE 1042-Methyl-5-(2-{4-[3-(4-methylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)quinazoline(E104)

The title compound was prepared from5-{2-[4-(3-bromobenzylidene)piperidin-1-yl]ethoxy}-2 methylquinazolinein a manner similar to Example 58.

Mass spectrum (API⁺): Found 458 (MH⁺). C₂₈H₃₅N₅O requires 457.

¹H NMR (CDCl₃) δ: 2.35 (3H, s), 2.42 (2H, m), 2.58 (6H, m), 2.62 (2H,m), 2.74 (2H, m), 2.88 (3H s), 2.99 (2H, m), 3.21 (4H, m), 4.33 (2H, m),6.28 (1H, bs), 6.71 (1H, m), 6.76 (1H, m), 6.79 (1H m), 6.87 (1H, d J8),7.20 (1H, J 8), 7.50 (1H, d J8), 7.74 (1H, J 8), 9.65 (1H, s).

EXAMPLE 1052-Methyl-5-(2-{4-[3-(4-methylpiperazin-1-yl)benzyl]piperidin-1-yl}ethoxy)quinazoline(E105)

The title compound was prepared from2-methyl-5-(2-{4-[3-(4-methylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)quinazolinein a manner similar to Example 60.

Mass spectrum (API⁺): Found 460 (MH⁺). C₂₈H₃₇N₅O requires 459.

¹H NMR (CDCl₃) δ: 1.34 (2H, m), 1.54 (1H, m) 1.67 (2H, m), 2.14 (2H, m),2.35 (3H, s), 2.49 (2H, J 7), 2.58 (4H, m), 2.88 (3H, s), 2.93 (2H, m),3.02 (2H, m), 3.21 (4H, m), 4.30 (2H, m), 6.50 (1H m), 6.75 (2H, m),6.85 (1H, d J8), 7.16 (1H, m), 7.48 (1H, m), 7.74 (1H, m), 9.63 (1H, s).

EXAMPLE 1064-Methyl-1-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)piperazin-2-one(E106)

A solution ofC-[(2-chloroethyl)methylamino]-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamide(130 mg, 0.26 mmol) in DMF (5 ml) was treated with sodium hydride (14mg, 60% suspension in oil, 0.35 mmol) at ambient temperature. Theresulting mixture was stirred, under argon, at ambient temperature for 2h, and then partitioned between ethyl acetate (5 ml) and water (3×5 ml).The organic layer was separated and added to a 10 g silica column andeluted from 0-10% methanol in ethyl acetate and 2% 0.880 ammonia in 10%methanol in ethyl acetate to give the title compound (28 mg, 23%) as ayellow oil.

Mass spectrum (API⁺): Found 473 (MH⁺). C₂₉N₃₆H₃₆N₄O₂ requires 472.

¹H NMR (CDCl₃) δ: 1.35 (2H, m), 1.55 (1H, m), 1.68 (2H, m), 2.13 (2H,m), 2.40 (3H, s), 2.54 (2H, J 7), 2.72 (3H, s), 2.78 (2H, m), 2.88 (2H,m), 2.92 (2H, m), 3.03 (2H, m), 3.69 (2H, m), 4.27 (2H m), 6.79 (1H, m),7.04-7.12 (2H, m), 7.27 (3H, m), 7.56 (2H, m), 8.42 (1H, d J9).

EXAMPLE 1074-Benzyl-1-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl)phenyl)piperazin-2-one

The title compound was prepared fromC-[benzyl-(2-chloroethyl)amino]-N-(3-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)acetamidein a manner similar to Example 106.

Mass spectrum (API⁺): Found 549 (MH⁺). C₃₅H₄₀N₄O₂ requires 548.

¹H NMR (CDCl₃) 8:1.65 (2H, m), 1.77 (3H, m), 2.47 (2H, m), 2.58 (2H, m),2.73 (3H, s), 2.80 (2H m), 3.22 (2H, m), 3.33 (2H, s), 3.37 (2H, m),3.63 (2H, s), 3.67 (2H, m), 4.49 (2H, m), 6.82 (1H, d 8), 7.03 (1H, m),7.08 (1H, m), 7.13 (1H, m), 7.25-7.36 (7H, m), 7.56 (1H, t J 8), 7.63(1H, m), 8.3 (1H, d J8).

EXAMPLE 1082-Methyl-5-{2-[4-(3-pyrazol-1-ylbenzylidene)piperidin-1-yl]ethoxy}quinoline(E108)

The title compound was prepared from4-(3-pyrazol-1-ylbenzylidene)piperidine and 5-(2bromoethoxy)-2-methylquinoline in an analogous manner to Example 1.

Mass spectrum (API⁺): Found 424 (MH⁺). C₂₇H₂₈N₄O requires 424.

¹H NMR (CDCl₃) δ: 2.46 (2H, m), 2.58 (2H, m), 2.65 (2H, m), 2.73 (3H,s), 2.76 (2H, m), 2.99 (2H m), 4.30 (2H, m), 6.34 (1H, s), 6.46 (1H, m),6.81 (1H, d J 7), 7.12 (1H, d J 8), 7.25 (1H, m), 7.3 (1H, t J8), 7.56(4H, m), 7.72 (1H, d J1), 7.91 (1H, d J 4), 8.44 (1H, d J 9).

EXAMPLE 1092-Methyl-5-{2-[4-(3-pyrazol-1-ylbenzyl)piperidin-1-yl]ethoxy}quinoline(E109)

The title compound was prepared from2-methyl-5-{2-[4-(3-pyrazol-1-yl-benzylidene)piperidin-1yl]ethoxy}quinoline in a manner similar to Example 60.

Mass spectrum (API⁺): Found 427 (MH⁺). C₂₇H₃₀N₄O requires 426.

¹H NMR (CDCl₃) δ: 1.38 (2H, m), 1.62 (1H, m), 1.69 (2H, m), 2.15 (2H,m), 2.61 (2H, d J 7), 2.7 (3H, s), 2.93 (2H, m), 3.04 (2H, m), 4.27 (2H,m), 6.46 (1H, m), 6.79 (1H, d J 7), 7.07 (1H, d J 8 7.24 (1H, d J 9),7.34 (1H, t J 8), 7.47 (1H, m), 7.56 (3H, m), 7.72 (1H, d J 1), 7.92(1H, d J 2), 8.4 (1H, d J 9).

EXAMPLE 110N-(3-Chloro-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}phenyl)methanesulfonamide(E110)

The title compound was prepared from3-chloro-5-{1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}anilineusing analogous routes and intermediates to those used in thepreparation of Example 3.

Mass spectrum (API⁺): Found 487 (MH⁺). C₂₅H₂₈ClN₃O₃S requires 486.

¹H NMR (400 MHz, CDCl₃) δ 2.42 (2H, t J 5.6), 2.51 (2H, t J 5.2), 2.65(2H, t J 5.2), 2.73 (3H, s), 2.74 (2H, t J 6.4), 2.99 (2H, t J 5.6),3.04 (3H, s), 4.30 (2H, t J 5.6), 6.19 (1H, s), 6.81 (1H, d J 6.4), 6.92(1H, s), 7.01 (1H, s), 7.06 (1H, s), 7.26 (1H, t J 4.8), 7.54-7.62 (2H,m), 8.44 (1H, d J 8.4).

EXAMPLE 1115-(2-{4-[3-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-fluorobenzylidene]piperidin-1-ylethoxy)-2-methylquinoline(E111)

The title compound was prepared using analogous routes and intermediatesto those used in the preparation of Example 58.

Mass spectrum (API⁺): Found 489 (MH⁺). C₃₀H₃₇N₄FO requires 488.

¹H NMR (400 MHz, CDCl₃) δ 1.1 (6H, d, J 6.4), 2.30 (2H, t J 10.8), 2.42(2H, t J 5.2), 2.53 (2H, t J 5.2), 2.63 (2H, t J 5.2), 2.73 (3H, s) 2.74(2H, t J 5.6), 2.98 (2H, t J 5.6), 3.10-3.12 (2H, m), 3.29-3.32 (2H, d J12.4), 4.30 (2H, t J 5.6), 6.232 (1h, s), 6.73-6.76 (2H, m), 6.81 (1H, dJ 7.2), 6.92-6.97 (1H, m), 7.25 (1H, d J 8.8), 7.54-7.62 (2H, m), 8.44(1H, d J 8.8).

EXAMPLE 1125-(2-{4-[4-Fluoro-3-((R)-3-methylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)-2-methylquinoline(E112)

The title compound was prepared using analogous routes and intermediatesto those used in the preparation of Example 58.

Mass spectrum (API⁺): Found 475 (MH⁺). C₂₉H₃₅N₄FO requires 474.

¹H NMR (400 MHz, CDCl₃) δ1.10 (3H, d J 6.4), 2.37 (1H, m), 2.41 (2H, tJ5.2), 2.53 (2H, t J 5.2), 2.63 (2H, t J 5.2), 2.73 (3H, s), 2.74 (2H, tJ 5.6), 2.98 (2H, t J 5.6) 3.06 (4H, m), 3.31 (2H, d J 11.6), 4.30 (2H,t J 5.6), 6.23 (1H, s), 6.75 (2H, m), 6.81 (2H, d J 7.2), 6.92-6.97 (1H,m), 7.25 (1H, d J 8.4), 7.54-7.62 (2H, m), 8.44 (1H, d J 8.8).

EXAMPLE 1135-(2-{4-[4-Fluoro-3-((S)-3-methylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)-2-methylquinoline(E113)

The title compound was prepared using analogous routes and intermediatesto those used in the preparation of Example 58.

Mass spectrum (API⁺): Found 475 (MH⁺). C₂₉H₃₅N₄FO requires 474.

¹H NMR (400 MHz, CDCl₃) δ 1.09 (3H, d J 6.2), 2.41 (3H, m), 2.53 (2H, tJ 5.4), 2.63 (2H, t J 5.4), 2.73 (3H, s), 2.75 (3H, m), 2.98 (2H, t J5.7), 3.08-3.12 (3H, m), 3.31 (2H, d J 11.5), 4.30 (2H, t J 5.7), 6.23(2H, s), 6.74-6.77 (2H, m), 6.81 (1H, d J 6.6), 6.92-6.97 (1H, m), 7.25(1H, t J 3.6), 7.53-7.61 (2H, m), 8.44 (1H, d J 7.7).

EXAMPLE 1145-(2-(4-[4-Fluoro-3-(4-methylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)-2-methylquinoline(E114)

The title compound was prepared using analogous routes and intermediatesto those used in the preparation of Example 58.

Mass spectrum (API⁺): Found 475 (MH⁺). C₂₉H₃₅FN₄O requires 474.

¹H NMR (400 MHz, CDCl₃) δ 2.38 (3H, s), 2.42 (2H, t J 5.2), 2.53 (2H, tJ 5.4), 2.64 (6H, t J 4.7), 2.73 (3H, s), 2.74 (2H, t J 5.5), 2.99 (2H,t J 5.7), 3.13 (4H, t 4.7), 4.30 (2H, t J 5.7), 6.23 (1H, s), 6.75-6.77(2H, m), 6.81 (1H, d J 7.5), 6.92-6.98 (1H, m), 7.26 (1H, s), 7.53-7.62(2H, m), 8.44 (1H, d J 8.6).

EXAMPLE 1155-(2{4-[3-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-4-fluorobenzyl]piperidin-1-yl}ethoxy)-2-methylquinoline(E115)

The title compound was prepared from5-(2-{4-[3-((3R,5S)-3,5-dimethylpiperazin-1-yl)-4-fluorobenzylidene]piperidin-1-ylethoxy)-2-methylquinolineusing the method of Example 60.

Mass spectrum (API⁺): Found 491 (MH⁺). C₃₀H₃₉FN₄O requires 490.

¹H NMR (400 MHz, CDCl₃) δ 1.11 (6H, d J6.4), 1.29-1.33 (2H, m), 1.50(1H, m), 1.64 (2H, d J 12.4), 2.14 (2H, t J 10.0), 2.29 (2H, t J 10.8),2.47 (2H, d J 6.8), 2.73 (3H, s), 2.93 (2H, t J 5.6), 3.03 (2H, d J11.6), 3.09-3.14 (2H, m), 3.29 (2H, d J 10.4), 4.27 (2H, t J 5.6), 6.66(2H, m), 6.79 (1H, d J 7.6), 6.88-6.93 (1H, m), 7.25 (1H, d), 7.52-7.60(2H, m), 8.42 (1H, d J 8.4).

EXAMPLE 1165-(2-(4-[4-Fluoro-3-(4-methylpiperazin-1-yl)benzyl]piperidin-1-yl}ethoxy)-2-methylquinoline(E116)

The title compound was prepared from5-(2-{4-[4-fluoro-3-(4-methylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)-2-methylquinolineusing the method of Example 60.

Mass spectrum (API⁺): Found 477 (MH⁺). C₂₉H₃₇N₄° F. requires 476.

¹H NMR (400 MHz, CDCl₃) δ 1.36 (2H, J 12.4), 1.49 (1H, m br), 1.65 (2H,d J 12.5), 2.16 (2H, t J 11.6), 2.36 (3H, s), 2.47 (2H, d J 7.0), 2.61(4H, t J 4.4), 2.72 (3H, s), 2.94 (2H, t J 5.7), 3.05 (2H, d J 11.6),3.12 (4H, t J 4.4), 4.28 (2H, t J 5.7), 6.69 (2H, m), 6.79 (2H, d J7.4), 6.91 (1H, m), 7.57 (2H, m), 8.42 (1H, d J 8.6).

EXAMPLE 1175-(2{4-[4-Fluoro-3-(4-methylpiperazin-1-yl)benzyl]piperidin-1-yl}ethoxy)-2-methylquinazoline(E117)

The title compound was prepared1-(2-fluoro-5-(piperidin-4-ylmethyl)phenyl)-4-methylpiperazine and5-[2-(methanesulfonyloxy)ethoxy]-2-methylquinazoline according themethod of Example 48.

Mass spectrum (API⁺): Found 478 (MH⁺). C₂₈H₃₆N₅° F. requires 477.

¹H NMR (400 MHz, CDCl₃) δ 1.36 (2H, t br J 11.6), 1.50 (1H, m br), 1.65(2H, d J 12.4), 2.2 (2H, t J 11.2), 2.39 (3H, s), 2.47 (2H, d J 6.8),2.65 (4H, br), 2.88 (3H, s), 2.97 (2H, t J 5.6), 3.05 (2H, d J 11.2),3.15 (4H, t J4.4), 4.33 (2H, t J5.6), 6.68 (2H, m), 6.84-6.94 (2H, m),7.49 (1H, d J 8.0), 7.74 (1H, t J 8.4), 9.63 (1H, s).

EXAMPLE 1185-(2-{4-[4-Fluoro-3-(4-methylpiperazin-1-yl)benzyl]piperidin-1-yl}ethoxy)-2-trifluoromethylquinoline(E118)

The title compound was prepared1-(2-fluoro-5-(piperidin-4-ylmethyl)phenyl)₄-methylpiperazine and5-(2-bromoethoxy)-2-(trifluoromethyl)quinoline according the method ofExample 2.

Mass spectrum (API⁺): Found 531 (MH⁺). C₂₉H₃₄N₄OF₄ requires 530.

¹H NMR (400 MHz, CDCl₃) δ 1.26-1.39 (2H, m), 1.66 (2H, d J 12.8), 1.90(1H, br), 2.17 (2H, t J 11.5), 2.38 (3H, s), 2.48 (2H, d J 6.92), 2.63(4H, s br), 2.97 (2H, t J 5.6), 3.05 (2H, d J 11.3), 3.13 (4H, s br),4.32 (2H, t J 5.6), 6.68 (2H, m), 6.88-6.97 (2H, m), 7.68-7.72 (2H, m),7.79 (1H, d J8.6), 8.74 (1H, d J8.8).

EXAMPLE 1195-(2-(4-[4-Fluoro-3-((R)-3-methylpiperazin-1-yl)benzyl]piperidin-1-yl}ethoxy)-2-methylquinoline(E119)

The title compound was prepared from5-(2-{4-[4-fluoro-3-((R)-3-methylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)-2-methylquinolineusing the method of Example 60.

Mass spectrum (API⁺): Found 477 (MH⁺). C₂₉H₃₇FN₄O requires 476.

¹H NMR (400 MHz, CDCl₃) δ:1.1 (3H, d), 1.25-1.33 (4H, m), 1.49 (1H, m),1.63 (2H, br d), 2.13 (2H, t), 2.35 (1H, t), 2.47 (2H, d), 2.69 (1H, m),2.71 (3H, s), 2.92 (2H, t), 3.01-3.11 (4H, m), 3.31 (2H, br d), 4.27(2H, t), 6.67 (2H, d), 6.78 (1H, d), 6.90 (1H, m), 7.23 (1H, d),7.52-7.60 (2H, m), 8.42 (1H, d).

EXAMPLE 120N-(3-{4-Cyano-1-[2-(2-methylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)methanesulfonamide(E120)

The title compound was prepare from tert-butyl4-cyano-4-(3-nitrobenzyl)piperidine-1-carboxylate using analogous routesand intermediates to those used to prepare Example 3.

Mass spectrum (API⁺): Found 479 (MH⁺). C₂₆H₃₀N₄O₃S requires 478.

¹H NMR (400 MHz, CDCl₃) δ 1.69 (2H, t J 13.2), 1.88 (2H, d J 11.6), 2.51(2H, t J 12.4), 2.73 (3H, s), 2.85 (2H, s), 2.98 (2H, t J 5.6), 3.04(3H, s), 3.07 (2H, t J 5.6), 4.26 (2H, t J 5.6), 6.50 (1H, s br), 6.79(1H, d J7.2), 7.08 (1H, d J7.6), 7.14 (1H, d J7.2), 7.26 (1H, d J 6),7.32 (1H, t J 7.6), 7.58 (2H, m), 8.41 (1H, d J 8.8).

EXAMPLE 1215-(2-{4-[3-(4-Methylpiperazin-1-yl)benzylidene]piperidin-1-yl}ethoxy)-2-cyanoquinoline(E121)

The title compound was prepared from3-{1-[2-(2-cyanoquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}bromobenzeneand 4-methylpiperazine using a similar procedure to Example 58.

Mass spectrum (API+): Found 468 (MH⁺). C₂₉H₃₃N₅₀ requires 467.

¹H NMR (CDCl₃) δ: 2.35 (3H, s), 2.38-2.44 (2H, m), 2.52-2.64 (8H, m),2.70-2.77 (2H, m), 2.95-3.02 (2H, m), 3.17-3.22 (4H, m), 4.33 (2H, t),6.28 (1H, s), 6.71 (1H, d), 6.75-6.80 (2H, m), 6.99 (1H, dd), 7.20 (1H,t), 7.67 (1H, d), 7.70-7.78 (2H, m), 8.70 (1H, d).

EXAMPLE 122N-(3-{1-[2-(2-Methoxycarbonylquinolin-5-yloxy)ethyl]piperidin-4-ylmethyl}phenyl)methanesulfonamide(E122)

A solution of 5-(2-bromoethoxy)quinoline-2-carbonitrile (50 mg, 0.18mmol), N-[3-(piperidin-4-ylmethyl)phenyl]methanesulphonamidehydrochloride (95 mg, 0.25 mmol) and diisopropylethylamine (100 mg, 0.75mmol) in 2-propanol (10 ml) was heated under reflux for 48 h, thenconcentrated under vacuum. The residue was dissolved in a mixture ofmethanol (10 ml) and THF (5 ml), treated with 1M sodium hydroxide (5 ml)and stirred at room temperature for 1 h, then concentrated under vacuum.The residue was treated with 10% sodium carbonate solution, extractedwith ethyl acetate and the extract separated, dried (Na₂SO₄),concentrated under vacuum and then chromatographed on silca gel elutingwith 0-5% methanol/DCM to afford the title compound as a yellow oil (30mg, 36%).

Mass spectrum (API+): Found 498 (MH⁺). C₂₆H₃₁N₃O₅S requires 497.

¹H NMR (CDCl₃) δ: 1.27-1.40 (2H, m), 1.50-1.60 (1H, m), 1.66 (2H, br d),2.14 (2H, br t), 2.54 (2H, d), 2.94 (2H, t), 3.00 (3H, s), 3.03 (2H, brd), 4.08 (3H, s), 4.30 (2H, t), 6.50 (1H, br, NH), 6.90-7.05 (4H, m),7.25 (1H, t), 7.66 (1H, t), 7.87 (1H, d), 8.15 (1H, d), 8.69 (1H, d).

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein A is optionally substituted phenyl, naphthyl, indolyl,quinolinyl, quinazolinyl, indazolyl, isoquinolinyl or benzofuranyl; X iscarbon, Y is CH and

is a double bond; or X is CH, Y is CH₂ or oxygen and

is a single bond; or X is nitrogen, Y is CH₂ and

is a single bond; R1 is halogen, hydroxy, cyano, C₁₋₆alkyl,haloC₁₋₆alkyl or C₁₋₆alkoxy; a is 0, 1, 2, 3 or 4; R2 and R3, togetherwith the nitrogen atom to which they are attached, form a nitro group oran optionally substituted 3 to 7 membered heterocyclic group, or R2 andR3 are independently hydrogen, aroyl, C₁₋₆alkyl, C₁₋₆alkanoyl,fluoroC₁₋₆alkanoyl, C₁₋₆alkylsulfonyl, fluoroC₁₋₆alkylsulfonyl,carbamoyl, C₁₋₆alkylcarbamoyl, arylC₁₆alkyl or a group CO(CH₂)bnR4R5wherein b is 1, 2, 3 or 4 and R4 and R5 are independently hydrogen orc₁₆alkyl, or R4 and R5, together with the nitrogen atom to they areattached, form part of an optionally substituted 3 to 7 memberedheterocyclic group.
 2. A compound as claimed in claim 1, wherein A isquinolinyl or quinazolinyl.
 3. A compound as claimed in claim 2, whereinA is 5-(2-methyl)quinolinyl or 5-(2-methyl)quinazolinyl.
 4. A compoundas claimed in claim 1, wherein a is 0, 1 or
 2. 5. A compound as claimedin claim 1, wherein one of R2 and R3 is hydrogen or C₁₋₆alkyl(particularly methyl, ethyl or propyl) and the other is C₁₋₆alkanoyl,C₁₋₆alkylsulfonyl, haloC₁₋₆alkanoyl or C₁₋₆alkylcarbamoyl, or R2 and R3together with the nitrogen atom to which they are attached, form anoptionally substituted piperidinyl or piperazinyl group or a nitrogroup.
 6. A compound as claimed in claim 1 which is any of compoundsE1-E122 or a pharmaceutically acceptable salt thereof.
 7. A process forthe preparation of a compound of formula (I) as defined in claim 1 or apharmaceutically acceptable salt thereof, which process comprises: (a)the coupling of a compound of formula (II):

wherein A is as defined for formula (I) and L is a leaving group, and acompound of formula (III):

wherein a, R1, R2, R3, X, Y and

are as defined for formula (I); or (b) for a compound wherein X isnitrogen, the coupling of a compound of formula (IV):

wherein A is as defined for formula (I), and a compound of formula (V):

wherein a, R1, R2 and R3 are as defined for formula (I), or (c) aBuchwald reaction between a compound of formula (VI):

wherein L is a suitable leaving group and a, R1, X, Y and

are as defined for formula (I), and a compound of formula (VII):

wherein R2 and R3 are as defined for formula (I); and thereafteroptionally for process (a), (b) or (c): removing any protecting groupsand/or converting a compound of formula (I) into another compound offormula (I) and/or forming a pharmaceutically acceptable salt.
 8. Apharmaceutical composition comprising a compound as defined in claim 1,and a pharmaceutically acceptable diluent, carrier and/or excipient. 9.A process for preparing a composition as defined in claim 8, the processcomprising mixing a compound as defined in claim 1 with apharmaceutically acceptable diluent, carrier and/or excipient.
 10. Acompound or a composition as defined in claim 1 for use in therapy. 12.A compound or a composition as defined in claim 1 for use in thetreatment of a CNS disorder.
 13. A compound or a composition as definedin claim 1 for use in the treatment of depression or anxiety.
 14. Amethod of treating a CNS disorder in mammals including humans, whichcomprises administering to the sufferer a therapeutically safe andeffective amount of a compound or a composition as defined in claim 1.15. A method as claimed in claim 14, wherein the disorder is depressionor anxiety.
 16. Use of a compound or a composition as defined in claim 1in the manufacture of a medicament for use in the treatment of a CNSdisorder.
 17. The use as claimed in claim 16, wherein the disorder isdepression or anxiety.